2-keto amide derivatives as hiv attachment inhibitors

ABSTRACT

Compounds of Formula I, including pharmaceutically acceptable salts thereof: I useful as HIV attachment inhibitors.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the priority of U.S. Provisional ApplicationSer. No. 61/805,642 filed Mar. 27, 2013 which is herein incorporated byreference in its entirety.

FIELD OF THE INVENTION

This invention provides compounds having drug and bio-affectingproperties, their pharmaceutical compositions and methods of use. Inparticular, the invention herein is directed to 2-keto amide derivativesas HIV attachment inhibitors that possess unique antiviral activity, aswell as to methods for making these compounds, and to compositionscontaining these compounds.

BACKGROUND OF THE INVENTION

HIV-1 (human immunodeficiency virus-1) infection remains a major medicalproblem, with an estimated 45-50 million people infected worldwide atthe end of 2010. The number of cases of HIV and AIDS (acquiredimmunodeficiency syndrome) has risen rapidly. In 2005, approximately 5.0million new infections were reported, and 3.1 million people died fromAIDS. Currently available drugs for the treatment of HIV includenucleoside reverse transcriptase (RT) inhibitors zidovudine (or AZT orRETROVIR®), didanosine (or VIDEX®), stavudine (or ZERIT®), lamivudine(or 3TC or EPIVIR®), zalcitabine (or DDC or HIVID®), abacavir succinate(or ZIAGEN®), tenofovir disoproxil fumarate salt (or VIREAD®),emtricitabine (or FTC—EMTRIVA®); non-nucleoside reverse transcriptaseinhibitors: nevirapine (or VIRAMUNE®), delavirdine (or RESCRIPTOR®),efavirenz (or SUSTIVA®), etravirine (INTELENCE®) and rilpivirine(EDURANT®), and peptidomimetic protease inhibitors or approvedformulations: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir,lopinavir, KALETRA® (lopinavir and Ritonavir), darunavir, atazanavir(REYATAZ®) and tipranavir (APTIVUS®), and integrase inhibitors such asraltegravir (ISENTRESS®), and entry inhibitors such as enfuvirtide(T-20) (FUZEON®) and maraviroc (SELZENTRY®). Several single pillcombinations have been also approved, which include COMBIVIR® (containslamivudine and zidovudine), TRIZIVIR® (contains abacavir, zidovudine,and lamivudine), EPZICOM® (contains abacavir and lamivudine), TRUVADA®(contains tenofovir disoproxil fumarate and emtricitabine), ATRIPLA®(contains efavirenz, emtricitabine and tenofovir disoproxil fumarate)and COMPLERA® (contains emtricitabine, rilpivirine, and tenofovirdisoproxil fumarate).

Each of these drugs can only transiently restrain viral replication ifused alone. However, when used in combination, these drugs have aprofound effect on viremia and disease progression. In fact, significantreductions in death rates among AIDS patients have been documented as aconsequence of the widespread application of combination therapy.However, despite these impressive results, 30 to 50% of patients mayultimately fail combination drug therapies. Insufficient drug potency,non-compliance, restricted tissue penetration and drug-specificlimitations within certain cell types (e.g., most nucleoside analogscannot be phosphorylated in resting cells) may account for theincomplete suppression of sensitive viruses. Furthermore, the highreplication rate and rapid turnover of HIV-1 combined with the frequentincorporation of mutations, leads to the appearance of drug-resistantvariants and treatment failures when sub-optimal drug concentrations arepresent. Therefore, novel anti-HIV agents exhibiting distinct resistancepatterns, and favorable pharmacokinetic as well as safety profiles areneeded to provide more treatment options. Improved HIV fusion inhibitorsand HIV entry coreceptor antagonists are two examples of new classes ofanti-HIV agents further being studied by a number of investigators.

HIV attachment inhibitors are a novel subclass of antiviral compoundsthat bind to the HIV surface glycoprotein gp120, and interfere with theinteraction between the surface protein gp120 and the host cell receptorCD4. Thus, they prevent HIV from attaching to the human CD4 T-cell, andblock HIV replication in the first stage of the HIV life cycle. Theproperties of HIV attachment inhibitors have been improved in an effortto obtain compounds with maximized utility and efficacy as antiviralagents. A disclosure describing indoles of which the structure shownbelow for BMS-705 is representative, has been disclosed in U.S. Pat. No.6,469,006 (Antiviral Indoleoxoacetyl Piperazine Derivatives).

Two other compounds, referred to in the literature as BMS-806 andBMS-043 have been described in both the academic and patent art:

Some description of their properties in human clinical trials has beendisclosed in the literature.

It should be noted that in all three of these structures, a piperazineamide (in these three structures a piperazine phenyl amide) is presentand this group is directly attached to an oxoacetyl moiety. Theoxoacetyl group is attached at the 3-position of 4-fluoro indole inBMS-705 and to the 3 position of substituted azaindoles in BMS-806 andBMS-043.

In an effort to obtain improved anti-HIV compounds, later publicationsdescribed in part, modified substitution patterns on the indoles andazaindoles. Examples of such efforts include: (1) novel substitutedindoleoxoacetic piperazine derivatives, (2) substitutedpiperazinyloxoacetylindole derivatives, and (3) substitutedazaindoleoxoacetic piperazine derivatives.

Replacement of these groups with other heteroaromatics or substitutedheteroaromatics or bicyclic hydrocarbons was also shown to be feasible.Examples include: (1) indole, azaindole and related heterocyclicamidopiperazine derivatives; (2) bicyclo[4.4.0] antiviral derivatives;and (3) diazaindole derivatives.

A select few replacements for the piperazine amide portion of themolecules have also been described in the art and among these examplesare (1) some piperidine alkenes; (2) some pyrrolidine amides; (3) someN-aryl or heteroaryl piperazines; (4) some piperazinyl ureas; and (5)some carboline-containing compounds.

Method(s) for preparing prodrugs for this class of compounds aredisclosed in Prodrugs of Piperazine and Substituted Piperidine AntiviralAgents (Ueda et al., U.S. Pat. No. 7,745,625 or WO 2005/090367 A1).

A published PCT patent application WO 2003/103607 A1 (Jun. 11, 2003)discloses an assay useful for assaying some HIV inhibitors.

Several published patent applications describe combination studies withpiperazine benzamide inhibitors, for example, U.S. Publication No.2005/0215543 (WO 2005/102328 A1), U.S. Publication No. 2005/0215544 (WO2005/102391 A1), and U.S. Pat. No. 7,776,863 (WO 2005/102392 A2).

A publication on new compounds in this class of attachment inhibitors(Wang, J. et al., Org. Biol. Chem., 3:1781-1786 (2005)) and a patentapplication on some more remotely related compounds have appeared in WO2005/016344.

Published patent applications WO 2005/016344 and WO 2005/121094 alsodescribe piperazine derivatives which are HIV inhibitors. Otherreferences in the HIV attachment area include U.S. Pat. No. 7,851,476,U.S. Pat. No. 7,396,830 and U.S. Pat. No. 7,504,399, WO 2007/103456, aswell as U.S. Pat. No. 7,348,337 and U.S. Pat. No. 7,354,924. Aliterature reference is J. Med. Chem., 50:6535 (2007).

What is therefore needed in the art are new HIV attachment inhibitorcompounds, and compositions thereof, which are efficacious against HIVinfection.

Of particular interest are new 2-keto amide derivatives as HIVattachment inhibitor compounds, described herein. The compounds of thepresent invention are 2-keto amide derivatives, which are believed to bestructurally distinct from the piperazine aryl amide HIV attachmentinhibitors set forth in the existing literature.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I below, thepharmaceutically acceptable salts and/or solvates (e.g., hydrates)thereof, their pharmaceutical formulations, and their use in patientssuffering from or susceptible to a virus such as HIV. The compounds ofFormula I, their pharmaceutically acceptable salts and/or solvates areeffective antiviral agents, particularly as inhibitors of HIV. They areuseful for the treatment of HIV and AIDS.

One embodiment of the present invention is directed to one or morecompounds of Formula I, including pharmaceutically acceptable saltsthereof:

wherein A is selected from the group consisting of:

wherein

a, b, c, d and e are independently selected from the group consisting ofhydrogen, halogen, cyano, nitro, COOR⁵⁶, XR⁵⁷, NA¹A², C(O)R⁷,C(O)NR⁵⁵R⁵⁶, B, Q, and E;B is selected from the group consisting of —C(═NR⁴⁶)(R⁴⁷), C(O)NR⁴⁰R⁴¹,aryl, heteroaryl, heteroalicyclic, S(O)₂R⁸, S(O)₂NR⁴⁰R⁴¹, C(O)R⁷,XR^(8a), (C₁₋₆)alkylNR⁴⁰R⁴¹, (C₁₋₆)alkylCOOR^(8b); wherein said aryl,heteroaryl, and heteroalicyclic are optionally substituted with one tothree same or different halogens or from one to three same or differentsubstituents selected from the group F; wherein aryl is napthyl orsubstituted phenyl; wherein heteroaryl is a mono or bicyclic systemwhich contains from 3 to 7 ring atoms for a mono cyclic system and up to12 atoms in a fused bicyclic system, including from 1 to 4 heteroatoms;wherein heteroalicyclic is a 3 to 7 membered mono cyclic ring which maycontain from 1 to 2 heteroatoms in the ring skeleton and which may befused to a benzene or pyridine ring;Q is selected from the group consisting of (C₁₋₆)alkyl, (C₃₋₇)cycloalkyland (C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl areoptionally substituted with one to three same or different halogens orfrom one to three same or different substituents selected from the groupconsisting of C(O)NR⁵⁵R⁵⁶, hydroxy, cyano and XR⁵⁷;E is selected from the group consisting of (C₁₋₆)alkyl, (C₃₋₇)cycloalkyland (C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl areindependently optionally substituted with a member selected from thegroup consisting of phenyl, heteroaryl, SMe, SPh, —C(O)NR⁵⁶R⁵⁷, C(O)R⁵⁷,SO₂(C₁₋₆)alkyl and SO₂Ph; wherein heteroaryl is a monocyclic systemwhich contains from 3 to 7 ring atoms, including from 1 to 4heteroatoms;F is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, (C₁₋₆)thioalkoxy, cyano, halogen, nitro,—C(O)R⁵⁷, benzyl, —NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl,—NR⁴²C(O)-aryl, —NR⁴²C(O)-heteroaryl, —NR⁴²C(O)-heteroalicyclic, a 4, 5,or 6 membered ring cyclic N-lactam, —NR⁴²S(O)₂—(C₁₋₆)alkyl,—NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴²S(O)2-aryl, —NR⁴²S(O)₂-heteroaryl,—NR⁴²S(O)2-heteroalicyclic, S(O)₂(C₁₋₆)alkyl, S(O)₂aryl, —S(O)2NR⁴²R⁴³,NR⁴²R⁴³, (C₁₋₆)alkylC(O)NR⁴²R⁴³, C(O)NR⁴²R⁴³, NHC(O)NR⁴²R⁴³,OC(O)NR⁴²R⁴³, NHC(O)OR⁵⁴, (C₁₋₆)alkylNR⁴²R⁴³, COOR⁵⁴, and(C₁₋₆)alkylCOOR⁵⁴; wherein said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl,heteroaryl, heteroalicyclic, (C₁₋₆)alkoxy, and aryloxy, are optionallysubstituted with one to nine same or different halogens or from one tofive same or different substituents selected from the group G; whereinaryl is phenyl; heteroaryl is a monocyclic system which contains from 3to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;G is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, cyano, halogen, nitro, —C(O)R⁵⁷, benzyl,—NR⁴⁸C(O)—(C₁₋₆)alkyl, —NR⁴⁸C(O)—(C₃₋₆)cycloalkyl, —NR⁴⁸C(O)-aryl,—NR⁴⁸C(O)-heteroaryl, —NR⁴⁸C(O)-heteroalicyclic, a 4, 5, or 6 memberedring cyclic N-lactam, —NR⁴⁸S(O)₂—(C₁₋₆)alkyl,—NR⁴⁸S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴⁸S(O)2-aryl, —NR⁴⁸S(O)₂-heteroaryl,—NR⁴⁸S(O)2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR⁴⁸R⁴⁹,(C₁₋₆)alkyl C(O)NR⁴⁸R⁴⁹, C(O)NR⁴⁸R⁴⁹, NHC(O)NR⁴⁸R⁴⁹, OC(O)NR⁴⁸R⁴⁹,NHC(O)OR^(54′), (C₁₋₆)alkylNR⁴⁸R⁴⁹, COOR⁵⁴, and (C₁₋₆)alkylCOOR⁵⁴;wherein aryl is phenyl; heteroaryl is a monocyclic system which containsfrom 3 to 7 ring atoms, including from 1 to 4 heteroatoms;heteroalicyclic is selected from the group consisting of aziridine,azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran,tetrahydropyran, azepine, and morpholine;R⁷ is selected from the group consisting of (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, and heteroalicyclic; wherein saidaryl, heteroaryl, and heteroalicyclic are optionally substituted withone to three same or different halogens or with from one to three sameor different substituents selected from the group F;wherein for R⁷, R⁸, R^(8a), R^(8b) aryl is phenyl; heteroaryl is a monoor bicyclic system which contains from 3 to 7 ring atoms for mono cyclicsystems and up to 10 atoms in a bicyclic system, including from 1 to 4heteroatoms; wherein heteroalicyclic is selected from the groupconsisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine;R⁸ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic; wherein said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic are optionally substituted withone to six same or different halogens or from one to five same ordifferent substituents selected from the group F or (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl;R^(8a) is a member selected from the group consisting of aryl,heteroaryl, and heteroalicyclic; wherein each member is independentlyoptionally substituted with one to six same or different halogens orfrom one to five same or different substituents selected from the groupF;R^(8b) is selected from the group consisting of hydrogen, (C₁₋₆)alkyland phenyl;X is selected from the group consisting of CR₁R₂, NH or NCH₃, O, and S;R⁴⁰ and R⁴¹ are independently selected from the group consisting of (a)hydrogen; (b) (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl substituted with one tothree same or different halogens or from one to two same or differentsubstituents selected from the group F or different functional groups:(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine,secondary amine, tertiary amine, ammonium, nitro, thiol, thioether,alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine,sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid,sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid,squarate, squaric acid, oxime, hydrazine, peroxide, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic; heteroaryl is selected from the group consisting of furanyl,thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl,pyrazinyl, pyridazinyl, and pyrimidinyl; and (c) (C₁₋₆)alkoxy, aryl,heteroaryl or heteroalicyclic; or R⁴⁰ and R⁴¹ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMepiperazine, piperidine, azepine, and morpholine; and wherein said aryl,heteroaryl, and heteroalicyclic are optionally substituted with one tothree same or different halogens or from one to two same or differentsubstituents selected from the group F; wherein for R⁴⁰ and R⁴¹ aryl isphenyl; heteroaryl is a monocyclic system which contains from 3 to 6ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine; provided when B is C(O)NR⁴⁰R⁴¹, at least one of R⁴⁰ and R⁴¹is not selected from groups (a) or (b);R⁴² and R⁴³ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, allyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl,heteroaryl and heteroalicyclic; or R⁴² and R⁴³ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMepiperazine, piperidine, azepine, and morpholine; and wherein said(C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl, heteroaryl, andheteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to two same or different substituentsselected from the group G or different functional groups: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl; wherein for R⁴² and R⁴³ aryl is phenyl;heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms,including from 1 to 4 heteroatoms; heteroalicyclic is a member selectedfrom the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;R⁴⁶ is selected from the group consisting of H, phenyl, aryl, heteroaryland (C₁₋₆)alkyl, OR⁵⁷, and NR⁵⁵R⁵⁶;R⁴⁷ is selected from the group consisting of H, amino, hydroxyl, phenyl,aryl, heteroaryl and (C₁₋₆)alkyl;R⁴⁸ and R⁴⁹ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, phenyl, aryl and heteroaryl;R⁵⁰ is selected from the group consisting of H, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, and benzyl; wherein each of said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl and benzyl are optionally substituted with one to threesame or different (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl,heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl,primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol,thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine,guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate,sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester,boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, amongwhich ether, peroxide, thioether, secondary amine, tertiary amine,ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be eitheracyclic or cyclic; heteroaryl is selected from the group consisting offuranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl,pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinylR⁵⁴ is selected from the group consisting of hydrogen and (C₁₋₆)alkyl;R^(54′) is (C₁₋₆)alkyl;R⁵⁵ and R⁵⁶ are independently selected from the group consisting ofhydrogen and (C₁₋₆)alkyl; andR⁵⁷ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,aryl, heteroaryl; andA¹ and A² are independently selected from hydrogen, (C₁₋₆)alkyl, aryl,heteroaryl, SO₂D¹, SO₂ND²D³, COD⁴, COCOD⁴, COOD⁴, COND⁵D⁶, COCOND⁵D⁶,COCOOD⁴, C(═ND⁷)D⁸, C(═ND⁹)ND¹⁰D¹¹;A¹ and A² can either never connect with each other, or conjoin to form aring structure;D¹, D², D³, D⁴, D⁵, D⁶, D⁷, D⁸, D⁹, D¹⁰, and D¹¹ are each independentlyselected from the group consisting of H, C₁-C₅₀ alkyl, C₃-C₅₀cycloalkyl, C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, phenyl, heteroaryl,C₃-C₅₀ amide and C₃-C₅₀ ether; heteroaryl is selected from the groupconsisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl,thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl,isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, tetrazinyl, triazinyl and triazolyl; provided the carbonatoms which comprise the carbon-carbon double bond of said C₃-C₂₀alkenyl or the carbon-carbon triple bond of said C₃-C₂₀ alkynyl are notthe point of attachment to the nitrogen to which D², D³, D⁵, D⁶, D⁷, D⁹,D¹⁰, and D¹¹ is attached; wherein said C₁-C₅₀ alkyl, C₃-C₅₀ cycloalkyl,C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, aryl, phenyl, heteroaryl, C₃-C₅₀amide and C₃-C₅₀ ether is optionally substituted with one to three sameor different of the following functionalities: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide and steroid, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic;Z is selected from the group of:

Z is also selected from the group of:

f and g are selected from the group consisting of H, (C₁-C₄) alkyl, and(C₃-C₆) cycloalkyl group, and wherein said alkyl or cycloalkyl group isoptionally substituted with one to three substitutions selected from thegroup of F, OH, OR, NR₁R₂, COOR, and CONR₁R₂; and wherein f and g can beconnected by carbon, oxygen, nitrogen or sulfur atom to form a ring;h and i are selected from the group consisting of H, (C₁-C₄) alkyl, and(C₃-C₆) cycloalkyl group. wherein said alkyl or cycloalkyl group isoptionally substituted with one to three substitutions selected from thegroup of F, OH, OR, NR₁R₂, COOR, and CONR₁R₂;and wherein h and i can be connected by a carbon, oxygen, nitrogen orsulfur atom to form a ring;j is selected from the group consisting of H, F, (C₁-C₄) alkyl, and(C₃-C₆) cycloalkyl group, and wherein said alkyl or cycloalkyl group isoptionally substituted with one to three substitutions selected from thegroup of F, OH, OR, NR₁R₂, COOR, and CONR₁R₂;l is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,(C₁₋₆)alkynyl, (C₃₋₆) cycloalkyl, halogen, cyano, —CONR³²R³³, —SO2 R³²,COR³², COOR⁸, tetrahydrofuryl, pyrrolidinyl, phenyl and heteroaryl;wherein said (C₁₋₆)alkyl, (C₁₋₆)alkynyl, phenyl and heteroaryl are eachindependently optionally substituted with one to three same or differentmembers selected from the group U; heteroaryl is selected from the groupconsisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl;m is selected from the group consisting of H, (C₁-C₄) alkyl optionallysubstituted with one to three substitutions selected from F, OH, OR,NR₁R₂, COOR, CONR₁R₂, (C₃-C₆) cycloalkyl optionally substituted with oneto three substitutions selected from F, OH, OR, NR₃R₄, COOR, CON R₃R₄,OR, halogen (attached to carbon only), and Group X;n, o, p, q, r, s, t and u are selected from the group consisting of H,F, (C₁-C₄) alkyl, and (C₃-C₆) cycloalkyl group, and wherein said alkylor cycloalkyl group is optionally substituted with one to threesubstitutions selected from the group of F, OH, OR, NR₁R₂, COOR, andCONR₁R₂;and wherein n, o, p, q, r, s, t and u can be connected by carbon,oxygen, nitrogen or sulfur atom to form a ring;u and v are selected from the group consisting of H, OH, NR_(1a)R_(2a),(C₁-C₄) alkyl optionally substituted with one to three substitutionsselected from F, OH, OR, NR₁R₂, COOR, CONR₁R₂, (C₃-C₆) cycloalkyloptionally substituted with one to three substitutions selected from F,OH, OR, NR₃R₄, COOR, CON R₃R₄, OR, halogen (attached to carbon only),and Group X;X₁ is selected from the group consisting of NH or NCH₃, O, and S;Ar is selected from the group consisting of phenyl and heteroaryl;wherein said phenyl and heteroaryl are independently optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from Group Y; heteroarylis selected from the group consisting of pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, and triazolyl;Group U is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl cyano, trimethylsilyl, phenyl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl,—NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²R⁴³, —C(O)NR⁴²R²⁴³, morpholino, nitro,—S(C₁₋₆)alkyl, —SPh, NR⁴²S(O)₂-alkyl, piperazinyl, N-Me piperazinyl,(CH2)_(n)COOR⁵⁴ and —CONR⁴²R⁴³; wherein said (C₁₋₆)alkyl, heteroaryl, orphenyl is optionally substituted with one to three same or differenthalogens or one to three methyl groups; heteroaryl is selected from thegroup consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl; heteroalicyclic is selected from the group consisting ofaziridine, azetidine, pyrrolidine, piperazine, N-methyl piperazine,piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine;Group X is selected from the group consisting of phenyl and heteroaryl;wherein said phenyl and heteroaryl are independently optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from Group D; heteroarylis selected from the group consisting of pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, and triazolyl;Group Y is selected from the group consisting of OH, OR, NR₁R₂, CN,COOR, CONR₁R₂, (C₁-C₄) alkyl, (C₃-C₆) cycloalkyl, and wherein said alkylor cycloalkyl group is optionally substituted with one to threesubstitutions selected from the group of F, OH, OR, NR₁R₂, COOR, andCONR₁R₂;R, R₁, R₂, R_(1a) and R_(2a) are independently H, (C₁-C₄) alkyl, (C₃-C₆)cycloalkyl group; wherein said alkyl or cycloalkyl group is optionallysubstituted with one to three substitutions selected from F, OH, OR,NR₃R₄, COOR, CON R₃R₄;and wherein R₁ and R₂ can be connected by carbon, oxygen, nitrogen orsulfur atom to form a ring; andR₃ and R₄ are independently H, (C₁-C₄) alkyl, (C₃-C₆) cycloalkyl group.

Another embodiment of the present invention is directed to a method fortreating mammals infected with a virus, especially wherein the virus isHIV, comprising administering to said mammal an antiviral effectiveamount of a compound of Formula I above, and one or morepharmaceutically acceptable carriers, excipients and/or diluents.Optionally, the compound of Formula I can be administered in combinationwith an antiviral effective amount of an AIDS treatment agent selectedfrom the group consisting of: (a) an AIDS antiviral agent; (b) ananti-infective agent; (c) an immunomodulator; and (d) other HIV entryinhibitors.

Another embodiment of the present invention is directed to apharmaceutical composition comprising an antiviral effective amount of acompound of Formula I and one or more pharmaceutically acceptablecarriers, excipients, diluents and optionally in combination with anantiviral effective amount of an AIDS treatment agent selected from thegroup consisting of: (a) an AIDS antiviral agent; (b) an anti-infectiveagent; (c) an immunomodulator; and (d) other HIV entry inhibitors.

In another embodiment of the invention there is provided one or moremethods for making the compounds of Formula I.

The present invention is directed to these, as well as other importantends, hereinafter described.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Since the compounds set forth herein may possess asymmetric centers andtherefore occur as mixtures of diastereomers and enantiomers, thepresent invention includes the individual diastereoisomeric andenantiomeric forms of the compounds of Formula I in addition to themixtures thereof.

DEFINITIONS

Unless otherwise specifically set forth elsewhere in the application,one or more of the following terms may be used herein, and shall havethe following meanings:

The term “H” refers to hydrogen, including its isotopes.

The term “C₁₋₆ alkyl” as used herein and in the claims (unless specifiedotherwise) mean straight or branched chain alkyl groups such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and thelike.

“C₁-C₄fluoroalkyl” refers to F-substituted C₁-C₄ alkyl wherein at leastone H atom is substituted with F atom, and each H atom can beindependently substituted by F atom.

“Halogen” refers to chlorine, bromine, iodine or fluorine.

An “aryl” or “Ar” group refers to an all carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. Examples,without limitation, of aryl groups are phenyl, napthalenyl andanthracenyl. The aryl group may be substituted or unsubstituted. Whensubstituted the substituted group(s) is preferably one or more selectedfrom alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy,thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen,nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, aminoand —NR^(x)R^(y), wherein R^(x) and R^(y) are independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl, aryl,carbonyl, C-carboxy, sulfonyl, trihalomethyl, and, combined, a five- orsix-member heteroalicyclic ring.

As used herein, a “heteroaryl” group refers to a monocyclic or fusedring (i.e., rings which share an adjacent pair of atoms) group having inthe ring(s) one or more atoms selected from the group consisting ofnitrogen, oxygen and sulfur and, in addition, having a completelyconjugated pi-electron system. Unless otherwise indicated, theheteroaryl group may be attached at either a carbon or nitrogen atomwithin the heteroaryl group. It should be noted that the term heteroarylis intended to encompass an N-oxide of the parent heteroaryl if such anN-oxide is chemically feasible as is known in the art. Examples, withoutlimitation, of heteroaryl groups are furyl, thienyl, benzothienyl,thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl,quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzoxazolyl,benzimidazolyl, indolyl, isoindolyl, pyrazinyl. diazinyl, pyrazine,triazinyl, tetrazinyl, and tetrazolyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thioalkoxy, thiohydroxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido,amino, and —WRY, wherein R^(x) and R^(y) are as defined above.

As used herein, a “heteroalicyclic” group refers to a monocyclic orfused ring group having in the ring(s) one or more atoms selected fromthe group consisting of nitrogen, oxygen and sulfur. Rings are selectedfrom those which provide stable arrangements of bonds and are notintended to encompass systems which would not exist. The rings may alsohave one or more double bonds. However, the rings do not have acompletely conjugated pi-electron system. Examples, without limitation,of heteroalicyclic groups are azetidinyl, piperidyl, piperazinyl,imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl,thiomorpholinyl and tetrahydropyranyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy,sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido,trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido, phosphonyl,amino and —WRY, wherein R^(x) and R^(y) are as defined above.

An “alkyl” group refers to a saturated aliphatic hydrocarbon includingstraight chain and branched chain groups. Preferably, the alkyl grouphas 1 to 20 carbon atoms (whenever a numerical range; e.g., “1-20”, isstated herein, it means that the group, in this case the alkyl group maycontain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to andincluding 20 carbon atoms). More preferably, it is a medium size alkylhaving 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having1 to 4 carbon atoms. The alkyl group may be substituted orunsubstituted. When substituted, the substituent group(s) is preferablyone or more individually selected from trihaloalkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy,heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, 0-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, andcombined, a five- or six-member heteroalicyclic ring.

A “cycloalkyl” group refers to an all-carbon monocyclic or fused ring(i.e., rings which share and adjacent pair of carbon atoms) groupwherein one or more rings does not have a completely conjugatedpi-electron system. Examples, without limitation, of cycloalkyl groupsare cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,cyclohexene, cycloheptane, cycloheptene and adamantane. A cycloalkylgroup may be substituted or unsubstituted. When substituted, thesubstituent group(s) is preferably one or more individually selectedfrom alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, silyl,guanyl, guanidino, ureido, phosphonyl, amino and —NR^(y) with R^(x) andR^(y) as defined above.

An “alkenyl” group refers to an alkyl group, as defined herein, havingat least two carbon atoms and at least one carbon-carbon double bond.

An “alkynyl” group refers to an alkyl group, as defined herein, havingat least two carbon atoms and at least one carbon-carbon triple bond.

A “hydroxy” group refers to an —OH group.

An “alkoxy” group refers to both an —O-alkyl and an —O-cycloalkyl groupas defined herein.

An “aryloxy” group refers to both an —O-aryl and an —O-heteroaryl group,as defined herein.

A “heteroaryloxy” group refers to a heteroaryl-O— group with heteroarylas defined herein.

A “heteroalicycloxy” group refers to a heteroalicyclic-O— group withheteroalicyclic as defined herein.

A “thiohydroxy” group refers to an —SH group.

A “thioalkoxy” group refers to both an S-alkyl and an —S-cycloalkylgroup, as defined herein.

A “thioaryloxy” group refers to both an —S-aryl and an —S-heteroarylgroup, as defined herein.

A “thioheteroaryloxy” group refers to a heteroaryl-S— group withheteroaryl as defined herein.

A “thioheteroalicycloxy” group refers to a heteroalicyclic-S— group withheteroalicyclic as defined herein.

A “carbonyl” group refers to a —C(═O)—R″ group, where R″ is selectedfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon), as each is definedherein.

An “aldehyde” group refers to a carbonyl group where R″ is hydrogen.

A “thiocarbonyl” group refers to a —C(═S)—R″ group, with R″ as definedherein.

A “Keto” group refers to a —CC(═O)C— group wherein the carbon on eitheror both sides of the C═O may be alkyl, cycloalkyl, aryl or a carbon of aheteroaryl or heteroalicyclic group.

A “trihalomethanecarbonyl” group refers to a Z₃CC(═O)— group with said Zbeing a halogen.

A “C-carboxy” group refers to a —C(═O)O—R″ groups, with R″ as definedherein.

An “O-carboxy” group refers to a R″C(—O)O-group, with R″ as definedherein.

A “carboxylic acid” group refers to a C-carboxy group in which R″ ishydrogen.

A “trihalomethyl” group refers to a —CZ₃, group wherein Z is a halogengroup as defined herein.

A “trihalomethanesulfonyl” group refers to an Z₃CS(═O)₂— groups with Zas defined above.

A “trihalomethanesulfonamido” group refers to a Z₃CS(═O)₂NR^(x)— groupwith Z as defined above and R^(x) being H or (C₁₋₆)alkyl.

A “sulfinyl” group refers to a —S(═O)—R″ group, with R″ being(C₁₋₆)alkyl.

A “sulfonyl” group refers to a —S(═O)₂R″ group with R″ being(C₁₋₆)alkyl.

A “S-sulfonamido” group refers to a —S(═O)₂NR^(X)R^(Y), with R^(X) andR^(Y) independently being H or (C₁₋₆)alkyl.

A “N-Sulfonamido” group refers to a R″S(═O)₂NR_(X)— group, with R_(x)being H or (C₁₋₆)alkyl.

A “O-carbamyl” group refers to a —OC(═O)N^(X)NR^(Y) group, with R^(X)and R^(Y) independently being H or (C₁₋₆)alkyl.

A “N-carbamyl” group refers to a R^(x)OC(═O)NR^(y) group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “O-thiocarbamyl” group refers to a —OC(═S)NR^(x)R^(y) group, withR^(x) and R^(y) independently being H or (C₁₋₆)alkyl.

A “N-thiocarbamyl” group refers to a R^(x)OC(═S)NR^(y)— group, withR^(x) and R^(y) independently being H or (C₁₋₆)alkyl.

An “amino” group refers to an —NH₂ group.

A “C-amido” group refers to a —C(═O)N^(x)NR^(y) group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “C-thioamido” group refers to a —C(═S)N^(x)NR^(y) group, with R^(x)and R^(y) independently being H or (C₁₋₆)alkyl.

A “N-amido” group refers to a RT(═O)NR^(y)— group, with R^(x) and R^(y)independently being H or (C₁₋₆)alkyl.

An “ureido” group refers to a —NR^(x)(═O)NR^(y)R^(y2) group, with R^(x),R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “guanidino” group refers to a —R^(K)NC(═N)NR^(y)R^(y2) group, withR^(x), R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “guanyl” group refers to a R^(x)R^(y)NC(═N)— group, with R^(x) andR^(y) independently being H or (C₁₋₆)alkyl.

A “cyano” group refers to a —CN group.

A “silyl” group refers to a —Si(R″)₃, with R″ being (C₁₋₆)alkyl orphenyl.

A “phosphonyl” group refers to a P(═O)(OR^(x))₂ with R^(x) being(C₁₋₆)alkyl.

A “hydrazino” group refers to a —NR^(x)NR^(y)R^(y2) group, with R^(x),R^(y), and R^(y2) independently being H or (C₁₋₆)alkyl.

A “4, 5, or 6 membered ring cyclic N-lactam” group refers to

Any two adjacent R groups may combine to form an additional aryl,cycloalkyl, heteroaryl or heterocyclic ring fused to the ring initiallybearing those R groups.

It is known in the art that nitrogen atoms in heteroaryl systems can be“participating in a heteroaryl ring double bond”, and this refers to theform of double bonds in the two tautomeric structures which comprisefive-member ring heteroaryl groups. This dictates whether nitrogens canbe substituted as well understood by chemists in the art. The disclosureand claims of the present invention are based on the known generalprinciples of chemical bonding. It is understood that the claims do notencompass structures known to be unstable or not able to exist based onthe literature.

Pharmaceutically acceptable salts and prodrugs of compounds disclosedherein are within the scope of the invention. The term “pharmaceuticallyacceptable salt” as used herein and in the claims is intended to includenontoxic base addition salts. Suitable salts include those derived fromorganic and inorganic acids such as, without limitation, hydrochloricacid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonicacid, acetic acid, tartaric acid, lactic acid, sulfuric acid, citricacid, maleic acid, fumaric acid, sorbic acid, aconitic acid, salicylicacid, phthalic acid, and the like. The term “pharmaceutically acceptablesalt” as used herein is also intended to include salts of acidic groups,such as a carboxylate, with such counterions as ammonium, alkali metalsalts, particularly sodium or potassium, alkaline earth metal salts,particularly calcium or magnesium, and salts with suitable organic basessuch as lower alkylamines (methylamine, ethylamine, cyclohexylamine, andthe like) or with substituted lower alkylamines (e.g.,hydroxyl-substituted alkylamines such as diethanolamine, triethanolamineor tris(hydroxymethyl)-aminomethane), or with bases such as piperidineor morpholine.

As stated above, the compounds of the invention also include “prodrugs”.The term “prodrug” as used herein encompasses both the term “prodrugesters” and the term “prodrug ethers”. The term “prodrug esters” asemployed herein includes esters and carbonates formed by reacting one ormore hydroxyls of compounds of Formula I with either alkyl, alkoxy, oraryl substituted acylating agents or phosphorylating agent employingprocedures known to those skilled in the art to generate acetates,pivalates, methylcarbonates, benzoates, amino acid esters, phosphates,half acid esters such as malonates, succinates or glutarates, and thelike.

As set forth above, the invention is directed to compounds of Formula I,including pharmaceutically acceptable salts thereof:

wherein A is selected from the group consisting of:

whereina, b, c, d and e are independently selected from the group consisting ofhydrogen, halogen, cyano, nitro, COOR⁵⁶, XR⁵⁷, NA¹A¹, C(O)R⁷,C(O)NR⁵⁵R⁵⁶, B, Q, and E;B is selected from the group consisting of —C(═NR⁴⁶)(R⁴⁷) C(O)NR⁴²R⁴³,aryl, heteroaryl, heteroalicyclic, S(O)₂R⁸, S(O)₂NR⁴⁰R⁴¹, C(O)R⁷,XR^(8a), (C₁₋₆)alkylNR⁴⁰R⁴¹, (C₁₋₆)alkylCOOR^(8b); wherein said aryl,heteroaryl, and heteroalicyclic are optionally substituted with one tothree same or different halogens or from one to three same or differentsubstituents selected from the group F; wherein aryl is napthyl orsubstituted phenyl; wherein heteroaryl is a mono or bicyclic systemwhich contains from 3 to 7 ring atoms for a mono cyclic system and up to12 atoms in a fused bicyclic system, including from 1 to 4 heteroatoms;wherein heteroalicyclic is a 3 to 7 membered mono cyclic ring which maycontain from 1 to 2 heteroatoms in the ring skeleton and which may befused to a benzene or pyridine ring;Q is selected from the group consisting of (C₁₋₆)alkyl, (C₃₋₂)cycloalkyland (C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl areoptionally substituted with one to three same or different halogens orfrom one to three same or different substituents selected from the groupconsisting of C(O)NR⁵⁵R⁵⁶, hydroxy, cyano and XR⁵⁷;E is selected from the group consisting of (C₁₋₆)alkyl, (C₃₋₂)cycloalkyland (C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and (C₂₋₆)alkenyl areindependently optionally substituted with a member selected from thegroup consisting of phenyl, heteroaryl, SMe, SPh, —C(O)NR⁵⁶R⁵⁷, C(O)R⁵⁷,SO₂(C₁₋₆)alkyl and SO₂Ph; wherein heteroaryl is a monocyclic systemwhich contains from 3 to 7 ring atoms, including from 1 to 4heteroatoms;F is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₂)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, (C₁₋₆)thioalkoxy, cyano, halogen, nitro,—C(O)R⁵⁷, benzyl, —NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl,—NR⁴²C(O)-aryl, —NR⁴²C(O)-heteroaryl, —NR⁴²C(O)-heteroalicyclic, a 4, 5,or 6 membered ring cyclic N-lactam, —NR⁴²S(O)₂—(C₁₋₆)alkyl,—NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴²S(O)2-aryl, —NR⁴²S(O)₂-heteroaryl,—NR⁴²S(O)2-heteroalicyclic, S(O)₂(C₁₋₆)alkyl, S(O)₂aryl, —S(O)2 NR⁴²R⁴³,NR⁴²R⁴³, (C₁₋₆)alkylC(O)NR⁴²R⁴³, C(O)NR⁴²R⁴³, NHC(O)NR⁴²R⁴³,OC(O)NR⁴²R⁴³, NHC(O)OR⁵⁴, (C₁₋₆)alkylNR⁴²R⁴³, COOR⁵⁴, and(C₁₋₆)alkylCOOR⁵⁴; wherein said (C₁₋₆)alkyl, (C₃₋₂)cycloalkyl, aryl,heteroaryl, heteroalicyclic, (C₁₋₆)alkoxy, and aryloxy, are optionallysubstituted with one to nine same or different halogens or from one tofive same or different substituents selected from the group G; whereinaryl is phenyl; heteroaryl is a monocyclic system which contains from 3to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;G is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, cyano, halogen, nitro, —C(O)R⁵⁷, benzyl,—NR⁴⁸C(O)—(C₁₋₆)alkyl, —NR⁴⁸C(O)—(C₃₋₆)cycloalkyl, —NR⁴⁸C(O)-aryl,—NR⁴⁸C(O)-heteroaryl, —NR⁴⁸C(O)-heteroalicyclic, a 4, 5, or 6 memberedring cyclic N-lactam, —NR⁴⁸S(O)₂—(C₁₋₆)alkyl,—NR⁴⁸S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴⁸S(O)2-aryl, —NR⁴⁸S(O)₂-heteroaryl,—NR⁴⁸S(O)2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR⁴⁸R⁴⁹,(C₁₋₆)alkyl C(O)NR⁴⁸R⁴⁹, C(O)NR⁴⁸R⁴⁹, NHC(O)NR⁴⁸R⁴⁹, OC(O)NR⁴⁸R⁴⁹,NHC(O)OR^(54′), (C₁₋₆)alkylNR⁴⁸R⁴⁹, COOR⁵⁴, and (C₁₋₆)alkylCOOR⁵⁴;wherein aryl is phenyl; heteroaryl is a monocyclic system which containsfrom 3 to 7 ring atoms, including from 1 to 4 heteroatoms;heteroalicyclic is selected from the group consisting of aziridine,azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran,tetrahydropyran, azepine, and morpholine;R⁷ is selected from the group consisting of (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, and heteroalicyclic; wherein saidaryl, heteroaryl, and heteroalicyclic are optionally substituted withone to three same or different halogens or with from one to three sameor different substituents selected from the group F;wherein for R⁷, R⁸, R^(8a), R^(8b) aryl is phenyl; heteroaryl is a monoor bicyclic system which contains from 3 to 7 ring atoms for mono cyclicsystems and up to 10 atoms in a bicyclic system, including from 1 to 4heteroatoms; wherein heteroalicyclic is selected from the groupconsisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine;R⁸ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂-6)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic; wherein said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl,aryl, heteroaryl, and heteroalicyclic are optionally substituted withone to six same or different halogens or from one to five same ordifferent substituents selected from the group F or (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl;R^(8a) is a member selected from the group consisting of aryl,heteroaryl, and heteroalicyclic; wherein each member is independentlyoptionally substituted with one to six same or different halogens orfrom one to five same or different substituents selected from the groupF;R^(8b) is selected from the group consisting of hydrogen, (C₁₋₆)alkyland phenyl;X is selected from the group consisting of CR₁R₂, NH or NCH₃, O, and S;R⁴⁰ and R⁴¹ are independently selected from the group consisting of (a)hydrogen; (b) (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl substituted with one tothree same or different halogens or from one to two same or differentsubstituents selected from the group F or different functional groups:(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine,secondary amine, tertiary amine, ammonium, nitro, thiol, thioether,alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine,sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid,sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid,squarate, squaric acid, oxime, hydrazine, peroxide, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic; heteroaryl is selected from the group consisting of furanyl,thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl,pyrazinyl, pyridazinyl, and pyrimidinyl; and (c) (C₁₋₆)alkoxy, aryl,heteroaryl or heteroalicyclic; or R⁴⁰ and R⁴¹ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMepiperazine, piperidine, azepine, and morpholine; and wherein said aryl,heteroaryl, and heteroalicyclic are optionally substituted with one tothree same or different halogens or from one to two same or differentsubstituents selected from the group F; wherein for R⁴⁰ and R⁴¹ aryl isphenyl; heteroaryl is a monocyclic system which contains from 3 to 6ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine; provided when B is C(O)NR⁴⁰R⁴¹, at least one of R⁴⁰ and R⁴¹is not selected from groups (a) or (b);R⁴² and R⁴³ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, allyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl,heteroaryl and heteroalicyclic; or R⁴² and R⁴³ taken together with thenitrogen to which they are attached form a member selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMepiperazine, piperidine, azepine, and morpholine; and wherein said(C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₃₋₇)cycloalkyl, aryl, heteroaryl, andheteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to two same or different substituentsselected from the group G or different functional groups: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl; wherein for R⁴² and R⁴³ aryl is phenyl;heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms,including from 1 to 4 heteroatoms; heteroalicyclic is a member selectedfrom the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine;R⁴⁶ is selected from the group consisting of H, phenyl, aryl, heteroaryland (C₁₋₆)alkyl, OR⁵⁷, and NR⁵⁵R⁵⁶;R⁴⁷ is selected from the group consisting of H, amino, hydroxyl, phenyl,aryl, heteroaryl and (C₁₋₆)alkyl;R⁴⁸ and R⁴⁹ are independently selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, phenyl, aryl and heteroaryl;R⁵⁰ is selected from the group consisting of H, (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, and benzyl; wherein each of said (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl and benzyl are optionally substituted with one to threesame or different (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl,heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl,primary amine, secondary amine, tertiary amine, ammonium, nitro, thiol,thioether, alcohol, ether, acid, aldehyde, ketone, amide, amidine,guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate,sulfuric acid, sulfamic acid, phosphate, phosphoric acid, boronic ester,boronic acid, squarate, squaric acid, oxime, hydrazine, peroxide, amongwhich ether, peroxide, thioether, secondary amine, tertiary amine,ammonium, ester, ketone, amide, amidine, oxime, hydrazine can be eitheracyclic or cyclic; heteroaryl is selected from the group consisting offuranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl,pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinylR⁵⁴ is selected from the group consisting of hydrogen and (C₁₋₆)alkyl;R^(54′) is (C₁₋₆)alkyl;R⁵⁵ and R⁵⁶ are independently selected from the group consisting ofhydrogen and (C₁₋₆)alkyl; andR⁵⁷ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,aryl, heteroaryl; andA¹ and A² are independently selected from hydrogen, (C₁₋₆)alkyl, aryl,heteroaryl, SO₂D¹, SO₂ND²D³, COD⁴, COCOD⁴, COOD⁴, COND⁵D⁶, COCOND⁵D⁶,COCOOD⁴, C(═ND⁷)D⁸, C(═ND⁹)ND¹⁰D¹¹;A¹ and A² can either never connect with each other, or conjoin to form aring structure;D¹, D², D³, D⁴, D⁵, D⁶, D⁷, D⁸, D⁹, D¹⁰, and D¹¹ are each independentlyselected from the group consisting of H, C₁-C₅₀ alkyl, C₃-C₅₀cycloalkyl, C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, phenyl, heteroaryl,C₃-C₅₀ amide and C₃-C₅₀ ether; heteroaryl is selected from the groupconsisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl,thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl,isoxazolyl, imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, tetrazinyl, triazinyl and triazolyl; provided the carbonatoms which comprise the carbon-carbon double bond of said C₃-C₂₀alkenyl or the carbon-carbon triple bond of said C₃-C₂₀ alkynyl are notthe point of attachment to the nitrogen to which D², D³, D⁵, D⁶, D⁷, D⁹,D¹⁰, and D¹¹ is attached; wherein said C₁-C₅₀ alkyl, C₃-C₅₀ cycloalkyl,C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, aryl, phenyl, heteroaryl, C₃-C₅₀amide and C₃-C₅₀ ether is optionally substituted with one to three sameor different of the following functionalities: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide and steroid, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic;Z is selected from the group of:

Z is also selected from the group of:

f and g are selected from the group consisting of H, (C₁-C₄) alkyl, and(C₃-C₆) cycloalkyl group, and wherein said alkyl or cycloalkyl group isoptionally substituted with one to three substitutions selected from thegroup of F, OH, OR, NR₁R₂, COOR, and CONR₁R₂;and wherein f and g can be connected by carbon, oxygen, nitrogen orsulfur atom to form a ring;h and i are selected from the group consisting of H, (C₁-C₄) alkyl, and(C₃-C₆) cycloalkyl group. wherein said alkyl or cycloalkyl group isoptionally substituted with one to three substitutions selected from thegroup of F, OH, OR, NR₁R₂, COOR, and CONR₁R₂;and wherein h and i can be connected by a carbon, oxygen, nitrogen orsulfur atom to form a ring;j is selected from the group consisting of H, F, (C₁-C₄) alkyl, and(C₃-C₆) cycloalkyl group, and wherein said alkyl or cycloalkyl group isoptionally substituted with one to three substitutions selected from thegroup of F, OH, OR, NR₁R₂, COOR, and CONR₁R₂;l is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,(C₁₋₆)alkynyl, (C₃₋₆) cycloalkyl, halogen, cyano, —CONR³²R³³, —SO2 R³²,COR³², COOR⁸, tetrahydrofuryl, pyrrolidinyl, phenyl and heteroaryl;wherein said (C₁₋₆)alkyl, (C₁₋₆)alkynyl, phenyl and heteroaryl are eachindependently optionally substituted with one to three same or differentmembers selected from the group U; heteroaryl is selected from the groupconsisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl;m is selected from the group consisting of H, (C₁-C₄) alkyl optionallysubstituted with one to three substitutions selected from F, OH, OR,NR₁R₂, COOR, CONR₁R₂, (C₃-C₆) cycloalkyl optionally substituted with oneto three substitutions selected from F, OH, OR, NR₃R₄, COOR, CON R₃R₄,OR, halogen (attached to carbon only), and Group X;n, o, p, q, r, s, t and u are selected from the group consisting of H,F, (C₁-C₄) alkyl, and (C₃-C₆) cycloalkyl group, and wherein said alkylor cycloalkyl group is optionally substituted with one to threesubstitutions selected from the group of F, OH, OR, NR₁R₂, COOR, andCONR₁R₂;and wherein n, o, p, q, r, s, t and u can be connected by carbon,oxygen, nitrogen or sulfur atom to form a ring;u and v are selected from the group consisting of H, OH, NR_(1a)R_(2a),(C₁-C₄) alkyl optionally substituted with one to three substitutionsselected from F, OH, OR, NR₁R₂, COOR, CONR₁R₂, (C₃-C₆) cycloalkyloptionally substituted with one to three substitutions selected from F,OH, OR, NR₃R₄, COOR, CON R₃R₄, OR, halogen (attached to carbon only),and Group X;X₁ is selected from the group consisting of NH or NCH₃, O, and S;Ar is selected from the group consisting of phenyl and heteroaryl;wherein said phenyl and heteroaryl are independently optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from Group Y; heteroarylis selected from the group consisting of pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, and triazolyl;Group U is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl cyano, trimethylsilyl, phenyl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl,—NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²R⁴³, —C(O)NR⁴²R²⁴³, morpholino, nitro,—S(C₁₋₆)alkyl, —SPh, NR⁴²S(O)₂-alkyl, piperazinyl, N-Me piperazinyl,(CH2)_(n)COOR⁵⁴ and —CONR⁴²R⁴³; wherein said (C₁₋₆)alkyl, heteroaryl, orphenyl is optionally substituted with one to three same or differenthalogens or one to three methyl groups; heteroaryl is selected from thegroup consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl; heteroalicyclic is selected from the group consisting ofaziridine, azetidine, pyrrolidine, piperazine, N-methyl piperazine,piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine;

Group X is selected from the group consisting of phenyl and heteroaryl;wherein said phenyl and heteroaryl are independently optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from Group D; heteroarylis selected from the group consisting of pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, and triazolyl;

Group Y is selected from the group consisting of OH, OR, NR₁R₂, CN,COOR, CONR₁R₂, (C₁-C₄) alkyl, (C₃-C₆) cycloalkyl, and wherein said alkylor cycloalkyl group is optionally substituted with one to threesubstitutions selected from the group of F, OH, OR, NR₁R₂, COOR, andCONR₁R₂;R, R₁, R₂, R_(1a) and R_(2a) are independently H, (C₁-C₄) alkyl, (C₃-C₆)cycloalkyl group; wherein said alkyl or cycloalkyl group is optionallysubstituted with one to three substitutions selected from F, OH, OR,NR₃R₄, COOR, CON R₃R₄;and wherein R₁ and R₂ can be connected by carbon, oxygen, nitrogen orsulfur atom to form a ring; andR₃ and R₄ are independently H, (C₁-C₄) alkyl, (C₃-C₆) cycloalkyl group.

More preferred compounds of Formula I include those which are selectedfrom the group of:

including pharmaceutically acceptable salts thereof. Of the foregoing,

are even more preferred, including pharmaceutically acceptable saltsthereof

The compounds of the present invention, according to all the variousembodiments described above, may be administered orally, parenterally(including subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques), by inhalation spray, orrectally, and by other means, in dosage unit formulations containingnon-toxic pharmaceutically acceptable carriers, excipients and diluentsavailable to the skilled artisan. One or more adjuvants may also beincluded.

Thus, in accordance with the present invention, there is furtherprovided a method of treatment, and a pharmaceutical composition, fortreating viral infections such as HIV infection and AIDS. The treatmentinvolves administering to a patient in need of such treatment apharmaceutical composition which contains an antiviral effective amountof one or more of the compounds of Formula I, together with one or morepharmaceutically acceptable carriers, excipients and/or diluents. Asused herein, the term “antiviral effective amount” means the totalamount of each active component of the composition and method that issufficient to show a meaningful patient benefit, i.e., inhibiting,ameliorating, or healing of acute conditions characterized by inhibitionof the HIV infection. When applied to an individual active ingredient,administered alone, the term refers to that ingredient alone. Whenapplied to a combination, the term refers to combined amounts of theactive ingredients that result in the therapeutic effect, whetheradministered in combination, serially or simultaneously. The terms“treat, treating, treatment” as used herein and in the claims meanspreventing, ameliorating or healing diseases associated with HIVinfection.

The pharmaceutical compositions of the invention may be in the form oforally administrable suspensions or tablets; as well as nasal sprays,sterile injectable preparations, for example, as sterile injectableaqueous or oleaginous suspensions or suppositories. Pharmaceuticallyacceptable carriers, excipients and/or diluents may be utilized in thepharmaceutical compositions, and are those utilized in the art ofpharmaceutical preparations.

When administered orally as a suspension, these compositions areprepared according to techniques typically known in the art ofpharmaceutical formulation and may contain microcrystalline cellulosefor imparting bulk, alginic acid or sodium alginate as a suspendingagent, methylcellulose as a viscosity enhancer, and sweeteners/flavoringagents known in the art. As immediate release tablets, thesecompositions may contain microcrystalline cellulose, dicalciumphosphate, starch, magnesium stearate and lactose and/or otherexcipients, binders, extenders, disintegrants, diluents, and lubricantsknown in the art.

The injectable solutions or suspensions may be formulated according toknown art, using suitable non-toxic, parenterally acceptable diluents orsolvents, such as mannitol, 1,3-butanediol, water, Ringer's solution orisotonic sodium chloride solution, or suitable dispersing or wetting andsuspending agents, such as sterile, bland, fixed oils, includingsynthetic mono- or diglycerides, and fatty acids, including oleic acid.

The compounds herein can be administered orally to humans in a dosagerange of 1 to 100 mg/kg body weight in divided doses, usually over anextended period, such as days, weeks, months, or even years. Onepreferred dosage range is 1 to 10 mg/kg body weight orally in divideddoses. Another preferred dosage range is 1 to 20 mg/kg body weight individed doses. It will be understood, however, that the specific doselevel and frequency of dosage for any particular patient may be variedand will depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular condition, and the host undergoing therapy.

Also contemplated herein are combinations of the compounds of Formula Iherein set forth, together with one or more agents useful in thetreatment of AIDS. For example, the compounds set forth herein may beeffectively administered, whether at periods of pre-exposure and/orpost-exposure, in combination with effective amounts of the AIDSantivirals, immunomodulators, anti-infectives, or vaccines, such asthose in the following non-limiting table:

Drug Name Manufacturer Indication ANTIVIRALS Rilpivirine Tibotec HIVinfection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor)COMPLERA ® Gilead HIV infection, AIDS, ARC; combination withemtricitabine, rilpivirine, and tenofovir disoproxil fumarate 097Hoechst/Bayer HIV infection, AIDS, ARC (non-nucleoside reversetranscriptase (RT) inhibitor) Amprenavir Glaxo Wellcome HIV infection,141 W94 AIDS, ARC GW 141 (protease inhibitor) Abacavir (1592U89) GlaxoWellcome HIV infection, GW 1592 AIDS, ARC (RT inhibitor) AcemannanCarrington Labs ARC (Irving, TX) Acyclovir Burroughs Wellcome HIVinfection, AIDS, ARC AD-439 Tanox Biosystems HIV infection, AIDS, ARCAD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxilGilead Sciences HIV infection AL-721 Ethigen ARC, PGL (Los Angeles, CA)HIV positive, AIDS Alpha Interferon Glaxo Wellcome Kaposi's sarcoma, HIVin combination w/Retrovir Ansamycin Adria Laboratories ARC LM 427(Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced BiotherapyAIDS, ARC Neutralizes pH Concepts Labile alpha aberrant (Rockville, MD)Interferon AR177 Aronex Pharm HIV infection, AIDS, ARC Beta-fluoro-ddANat'l Cancer Institute AIDS-associated diseases BMS-234475 Bristol-MyersSquibb/ HIV infection, (CGP-61755) Novartis AIDS, ARC (proteaseinhibitor) CI-1012 Warner-Lambert HIV-1 infection Cidofovir GileadScience CMV retinitis, herpes, papillomavirus Curdlan sulfate AJI PharmaUSA HIV infection Cytomegalovirus MedImmune CMV retinitis Immune globinCytovene Syntex Sight threatening Ganciclovir CMV peripheral CMVretinitis Darunavir Tibotec-J & J HIV infection, AIDS, ARC (proteaseinhibitor) Delaviridine Pharmacia-Upjohn HIV infection, AIDS, ARC (RTinhibitor) Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV Ind. Ltd.(Osaka, positive Japan) asymptomatic ddC Hoffman-La Roche HIV infection,AIDS, Dideoxycytidine ARC ddI Bristol-Myers Squibb HIV infection, AIDS,Dideoxyinosine ARC; combination with AZT/d4T DMP-450 AVID HIV infection,(Camden, NJ) AIDS, ARC (protease inhibitor) Efavirenz Bristol MyersSquibb HIV infection, (DMP 266, SUSTIVA ®) AIDS, ARC (—)6-Chloro-4-(S)-(non-nucleoside RT cyclopropylethynyl- inhibitor) 4(S)-trifluoro-methyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one, STOCRINE EL10 Elan Corp,PLC HIV infection (Gainesville, GA) Etravirine Tibotec/J & J HIVinfection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor)Famciclovir Smith Kline herpes zoster, herpes simplex GS 840 Gilead HIVinfection, AIDS, ARC (reverse transcriptase inhibitor) HBY097 HoechstMarion HIV infection, Roussel AIDS, ARC (non-nucleoside reversetranscriptase inhibitor) Hypericin VIMRx Pharm. HIV infection, AIDS, ARCRecombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta(Almeda, CA) sarcoma, ARC Interferon alfa-n3 Interferon Sciences ARC,AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIVpositive, also in combination with AZT/ddI/ddC ISIS 2922 ISISPharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HIV-assoc.diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC(reverse transcriptase inhibitor); also with AZT Lobucavir Bristol-MyersSquibb CMV infection Nelfinavir Agouron HIV infection, PharmaceuticalsAIDS, ARC (protease inhibitor) Nevirapine Boeheringer HIV infection,Ingleheim AIDS, ARC (RT inhibitor) Novapren Novaferon Labs, Inc. HIVinhibitor (Akron, OH) Peptide T Peninsula Labs AIDS Octapeptide(Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis, HIVPhosphonoformate Products, Inc. infection, other CMV infectionsPNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (proteaseinhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIVinfection, Tech (Houston, TX) AIDS, ARC Ritonavir Abbott HIV infection,AIDS, ARC (protease inhibitor) Saquinavir Hoffmann- HIV infection,LaRoche AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-MyersSquibb HIV infection, AIDS, Didehydrodeoxy- ARC Thymidine TipranavirBoehringer Ingelheim HIV infection, AIDS, ARC (protease inhibitor)Valaciclovir Glaxo Wellcome Genital HSV & CMV Infections VirazoleViratek/ICN asymptomatic HIV Ribavirin (Costa Mesa, CA) positive, LAS,ARC VX-478 Vertex HIV infection, AIDS, ARC Zalcitabine Hoffmann-LaRocheHIV infection, AIDS, ARC, with AZT Zidovudine; AZT Glaxo Wellcome HIVinfection, AIDS, ARC, Kaposi's sarcoma, in combination with othertherapies Tenofovir disoproxil, Gilead HIV infection, fumarate salt(VIREAD ®) AIDS, (reverse transcriptase inhibitor) EMTRIVA ® Gilead HIVinfection, (Emtricitabine) (FTC) AIDS, (reverse transcriptase inhibitor)COMBIVIR ® GSK HIV infection, AIDS, (reverse transcriptase inhibitor)Abacavir succinate GSK HIV infection, (or ZIAGEN ®) AIDS, (reversetranscriptase inhibitor) REYATAZ ® Bristol-Myers Squibb HIV infection(or atazanavir) AIDS, protease inhibitor FUZEON ® Roche/Trimeris HIVinfection (Enfuvirtide or T-20) AIDS, viral Fusion inhibitor LEXIVA ®GSK/Vertex HIV infection (or Fosamprenavir calcium) AIDS, viral proteaseinhibitor SELZENTRY ® Pfizer HIV infection Maraviroc; (UK 427857) AIDS,(CCR5 antagonist, in development) TRIZIVIR ® GSK HIV infection AIDS,(three drug combination) Sch-417690 (vicriviroc) Schering-Plough HIVinfection AIDS, (CCR5 antagonist, in development) TAK-652 Takeda HIVinfection AIDS, (CCR5 antagonist, in development) GSK 873140 GSK/ONO HIVinfection (ONO-4128) AIDS, (CCR5 antagonist, in development) IntegraseInhibitor Merck HIV infection MK-0518 AIDS Raltegravir TRUVADA ® GileadCombination of Tenofovir disoproxil fumarate salt (VIREAD ®) andEMTRIVA ® (Emtricitabine) Integrase Inhibitor Gilead/Japan Tobacco HIVInfection GS917/JTK-303 AIDS Elvitegravir in development Triple drugcombination Gilead/Bristol-Myers Squibb Combination of TenofovirATRIPLA ® disoproxil fumarate salt (VIREAD ®), EMTRIVA ®(Emtricitabine), and SUSTIVA ® (Efavirenz) FESTINAVIR ® OncolysBioPharma HIV infection AIDS in development CMX-157 Chimerix HIVinfection Lipid conjugate of AIDS nucleotide tenofovir GSK1349572 GSKHIV infection Integrase inhibitor AIDS IMMUNOMODULATORS AS-101Wyeth-Ayerst AIDS Bropirimine Pharmacia Upjohn Advanced AIDS AcemannanCarrington Labs, Inc. AIDS, ARC (Irving, TX) CL246, 738 Wyeth AIDS,Kaposi's Lederle Labs sarcoma FP-21399 Fuki ImmunoPharm Blocks HIVfusion with CD4+ cells Gamma Interferon Genentech ARC, in combinationw/TNF (tumor necrosis factor) Granulocyte Genetics Institute AIDSMacrophage Colony Sandoz Stimulating Factor Granulocyte Hoechst-RousselAIDS Macrophage Colony Immunex Stimulating Factor GranulocyteSchering-Plough AIDS, Macrophage Colony combination Stimulating Factorw/AZT HIV Core Particle Rorer Seropositive HIV Immunostimulant IL-2Cetus AIDS, in combination Interleukin-2 w/AZT IL-2 Hoffman-LaRocheAIDS, ARC, HIV, in Interleukin-2 Immunex combination w/AZT IL-2 ChironAIDS, increase in Interleukin-2 CD4 cell counts (aldeslukin) ImmuneGlobulin Cutter Biological Pediatric AIDS, in Intravenous (Berkeley, CA)combination w/AZT (human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA)sarcoma, ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA)sarcoma, ARC, PGL Imuthiol Diethyl Merieux Institute AIDS, ARC DithioCarbamate Alpha-2 Schering Plough Kaposi's sarcoma Interferon w/AZT,AIDS Methionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, IL)MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma Muramyl-Tripeptide GranulocyteAmgen AIDS, in combination Colony Stimulating w/AZT Factor Remune ImmuneResponse Immunotherapeutic Corp. rCD4 Genentech AIDS, ARC RecombinantSoluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS,ARC Soluble Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma Alfa2a AIDS, ARC, in combination w/AZT SK&F106528 Smith Kline HIV infectionSoluble T4 Thymopentin Immunobiology HIV infection Research Institute(Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNFw/gamma Interferon ANTI-INFECTIVES Clindamycin with Pharmacia Upjohn PCPPrimaquine Fluconazole Pfizer Cryptococcal meningitis, candidiasisPastille Squibb Corp. Prevention of Nystatin Pastille oral candidiasisOrnidyl Merrell Dow PCP Eflornithine Pentamidine LyphoMed PCP treatmentIsethionate (IM & IV) (Rosemont, IL) Trimethoprim AntibacterialTrimethoprim/sulfa Antibacterial Piritrexim Burroughs Wellcome PCPtreatment Pentamidine Fisons Corporation PCP prophylaxis Isethionate forInhalation Spiramycin Rhone-Poulenc Cryptosporidial diarrheaIntraconazole- Janssen-Pharm. Histoplasmosis; R51211 cryptococcalmeningitis Trimetrexate Warner-Lambert PCP Daunorubicin NeXstar, SequusKaposi's sarcoma Recombinant Human Ortho Pharm. Corp. Severe anemiaErythropoietin assoc. with AZT therapy Recombinant Human SeronoAIDS-related Growth Hormone wasting, cachexia Megestrol AcetateBristol-Myers Squibb Treatment of anorexia assoc. w/AIDS TestosteroneAlza, Smith Kline AIDS-related wasting Total Enteral Norwich EatonDiarrhea and Nutrition Pharmaceuticals malabsorption related to AIDS

Additionally, the compounds of the invention herein set forth may beused in combination with other HIV entry inhibitors. Examples of suchHIV entry inhibitors are discussed in Drugs of the Future,24(12):1355-1362 (1999); Cell, 9:243-246 (Oct. 29, 1999); and DrugDiscovery Today, 5(5):183-194 (May 2000) and Meanwell, N. A. et al.,“Inhibitors of the entry of HIV into host cells”, Curr. Op. Drug Disc.Dev, 6(4):451-461 (2003). Specifically the compounds can be utilized incombination with other attachment inhibitors, fusion inhibitors, andchemokine receptor antagonists aimed at either the CCR5 or CXCR4coreceptor.

It will be understood that the scope of combinations of the compoundsset forth herein with AIDS antivirals, immunomodulators,anti-infectives, HIV entry inhibitors or vaccines is not limited to thelist in the above Table but includes, in principle, any combination withany pharmaceutical composition useful for the treatment of AIDS.

Preferred combinations are simultaneous or alternating treatments with acompound of the present invention and an inhibitor of HIV proteaseand/or a non-nucleoside inhibitor of HIV reverse transcriptase. Anoptional fourth component in the combination is a nucleoside inhibitorof HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. A preferredinhibitor of HIV protease is REYATAZ® (active ingredient Atazanavir).Typically a dose of 300 to 600 mg is administered once a day. This maybe co-administered with a low dose of Ritonavir (50 to 500mgs). Anotherpreferred inhibitor of HIV protease is KALETRA®. Another usefulinhibitor of HIV protease is indinavir, which is the sulfate salt ofN-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)—N-(t-butylcarboxamido)-piperazinyl))-pentaneamideethanolate, and is synthesized according to U.S. Pat. No. 5,413,999.Indinavir is generally administered at a dosage of 800 mg three times aday. Other preferred protease inhibitors are nelfinavir and ritonavir.Another preferred inhibitor of HIV protease is saquinavir which isadministered in a dosage of 600 or 1200 mg tid. Preferred non-nucleosideinhibitors of HIV reverse transcriptase include efavirenz. Thesecombinations may have unexpected effects on limiting the spread anddegree of infection of HIV. Preferred combinations include those withthe following (1) indinavir with efavirenz, and, optionally, AZT and/or3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/or ddIand/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3)stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and141W94 and 1592U89; (5) zidovudine and lamivudine. (The preparation ofddC, ddI and AZT are also described in EP 0 484 071.)

In such combinations, the compounds set forth herein and other activeagents may be administered separately or in conjunction. In addition,the administration of one element may be prior to, concurrent to, orsubsequent to the administration of other agent(s).

Methods of Synthesis

The present invention comprises compounds of Formula I, theirpharmaceutical formulations, and their use in patients suffering from orsusceptible to HIV infection. The compounds of Formula I includepharmaceutically acceptable salts thereof. The compounds may be made bymethods available in the art, as well as those described after theAbbreviations and including variations within the skill of the art. Somereagents and intermediates are known in the art. Other reagents andintermediates can be made by methods known in the art using readilyavailable materials. The variables (e.g. numbered “R” substituents) usedto describe the synthesis of the compounds are intended only toillustrate how to make the compounds and are not to be confused withvariables used in the claims or in other sections of the specification.The following methods are for illustrative purposes and are not intendedto limit the scope of the invention.

Abbreviations

One or more of the following abbreviations, most of which areconventional abbreviations well known to those skilled in the art, maybe used throughout the description of the invention and the examples:

h=hour(s)rt=room temperaturemol=mole(s)mmol=millimole(s)g=gram(s)mg=milligram(s)mL=milliliter(s)TFA=trifluoroacetic Acid

DCE=1,2-Dichloroethane

CH₂Cl₂=dichloromethaneTPAP=tetrapropylammonium perruthenateTHF=tetrahydrofuranDEPBT=3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-oneDMAP=4-dimethylaminopyridineP-EDC=polymer supported 1-(3-dimethylaminopropyl)-3-ethylcarbodiimideEDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

DMF=N,N-dimethylformamide Hunig's Base=N,N-diisopropylethylamine

MCPBA=meta-chloroperbenzoic acidazaindole=1H-pyrrolo-pyridine4-azaindole=1H-pyrrolo[3,2-b]pyridine5-azaindole=1H-pyrrolo[3,2-c]pyridine6-azaindole=1H-pyrrolo[2,3-c]pyridine7-azaindole=1H-pyrrolo[2,3-b]pyridinePMB=4-methoxybenzylDDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinoneOTf=trifluoromethanesulfonoxyNMM=4-methylmorpholinePIP-COPh=1-benzoylpiperazineNaHMDS=sodium hexamethyldisilazideEDAC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimideTMS=trimethylsilylDCM=dichloromethaneDCE=dichloroethaneMeOH=methanolTHF=tetrahydrofuranEtOAc=ethyl acetateLDA=lithium diisopropylamideTMP-Li=2,2,6,6-tetramethylpiperidinyl lithiumDME=dimethoxyethaneDIBALH=diisobutylaluminum hydrideHOBT=1-hydroxybenzotriazoleCBZ=benzyloxycarbonylPCC=pyridinium chlorochromateTBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborateDEBPT=3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-oneBOP=benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate

Preparation of Compounds of Formula I

Preparation of template A-CO—CO—Cl and A-CO—CO—OH has been described indetail in WO-00076521, WO-0162255, WO-0204440, WO-02062423, WO-02085301,WO-03068221 and US-2004/0063744.

Standard conditions such as reacting amine with acyl halide 1 (Scheme1a) and carboxyl acid 3 (Scheme 1b) can be used to prepare the desiredamide products. Some general references of these methodologies anddirections for use are contained in “Comprehensive OrganicTransformation” by Richard C. Larock, Wiley-VCH, New York, 1989, 972(Carboxylic acids to amides), 979 (Acid halides to amides).

Scheme 1a depicts a general method for forming an amide from amine 2 andacyl chloride 1. An appropriate base (from catalytic to an excessamount) selected from sodium hydride, potassium carbonate,triethylamine, DBU, pyridine, DMAP or di-isopropyl ethyl amine was addedinto a solution of amine 2 and acyl chloride 1 in an appropriate solventselected from dichloromethane, chloroform, benzene, toluene, THF,diethyl ether, dioxane, acetone, N,N-dimethylformamide or pyridine atroom temperature. Then reaction was carried out at either roomtemperature or evaluated temperature up to 150° C. over a period of time(30 minutes to 48 hours) to afford the structure of Formula I. Someselected references involving such reactions include a) Indian J. Chem.,Sect B 1990, 29, 1077; 2) Chem. Sci. 1998, 53, 1216; 3) Chem. Pharm.Bull. 1992, 40, 1481; 4) Chem. Heterocycl. Compd. 2002, 38, 539.

Alternatively, as shown in Scheme 1b, an amine 2 can be coupled with anacid 3 using standard amide bond or peptide bond forming couplingreagents. Many reagents for amide bond couplings are known by an organicchemist skilled in the art and nearly all of these are applicable forrealizing coupled amide products. The combination of EDAC andtriethylamine in tetrahydrofuran or BOPCl and diisopropyl ethyl amine inchloroform have been utilized most frequently but DEPBT, or othercoupling reagents such as PyBop could be utilized. Another usefulcoupling condition employs HATU ((a) J. Chem. Soc. Chem Comm. 1994, 201;(b) J. Am. Chem. Soc. 1994, 116, 11580). Additionally, DEPBT(3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) andN,N-diisopropylethylamine, commonly known as Hunig's base, representsanother efficient method to form the amide bond and provide compounds ofFormula I. DEPBT is either purchased from Aldrich or prepared accordingto the procedure described in Organic Lett., 1999, 1, 91. Typically aninert solvent such as DMF or THF is used but other aprotic solventscould be used.

EXAMPLES

The following examples illustrate typical syntheses of the compounds ofFormula I as described generally above. These examples are illustrativeonly and are not intended to limit the invention in any way. Thereagents and starting materials are readily available to one of ordinaryskill in the art.

Chemistry Experimental Typical Procedures and Characterization ofSelected Examples

Unless otherwise stated, solvents and reagents were used directly asobtained from commercial sources, and reactions were performed under anitrogen atmosphere. Flash chromatography was conducted on Silica gel 60(0.040-0.063 particle size; EM Science supply). ¹H NMR spectra wererecorded on Bruker DRX-500f at 500 MHz (or Bruker DPX-300B or VarianGemini 300 at 300 MHz as stated). The chemical shifts were reported inppm on the δ scale relative to δTMS=0. The following internal referenceswere used for the residual protons in the following solvents: CDCl₃(δ_(H) 7.26), CD₃OD (δ_(H) 3.30), and DMSO-d6 (δ_(H) 2.50). Standardacronyms were employed to describe the multiplicity patterns: s(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), b(broad), app (apparent). The coupling constant (J) is in Hertz. AllLiquid Chromatography (LC) data were recorded on a Shimadzu LC-10ASliquid chromatograph using a SPD-10AV UV-Vis detector with MassSpectrometry (MS) data determined using a Micromass Platform for LC inelectrospray mode.

HPLC Method (i.e., Compound Isolation)

Compounds purified by preparative HPLC were diluted in methanol (1.2 mL)and purified using a Shimadzu LC-8A or LC-10A automated preparative HPLCsystem.

Typical Procedures and Characterization of Selected Examples:Intermediate ACOCOOH or ACOCOCl:

Preparation of intermediate ACOCOOH or ACOCOCl was described in theprevious published applications (W. Blair, et al. WO-200076521, O.Wallace, et al WO-200204440, T. Wang, et al. WO-200162255 and T. Wang,et al. WO-2002062423). Some examples of ACOCOOH are listed in below.

General Procedure to Prepare Formula I:

2-Keto acid (1 eq.), amine (1-5 eq.),3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) orO-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (1-5 eq.) or(2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (HATU) (1-5 eq.) and Hunig's Base or N-methylmorpholine (1-100 eq.) were combined in THF or DMF. The mixture wasstirred at room temperature or 115° C. for 17 hours. THF or DMF wasremoved via evaporation at reduced pressure and the residue waspartitioned between ethyl acetate and saturated NaHCO₃ aqueous solution.The aqueous layer was extracted with ethyl acetate. The organic phasewas combined and dried over anhydrous MgSO₄. Concentration in vacuoprovided a crude product, which was purified by titration, orrecrystallization, or silica gel column chromatography, or Shimadzuautomated preparative HPLC System.

2-Keto acyl chloride (1 eq.), amine (1-5 eq.) and Hunig's Base or Et₃N(1-100 eq.) were combined in THF or DMF. The mixture was stirred at roomtemperature or 115° C. for 17 hours. THF or DMF was removed viaevaporation at reduced pressure and the residue was partitioned betweenethyl acetate and saturated NaHCO₃ aqueous solution. The aqueous layerwas extracted with ethyl acetate. The organic phase was combined anddried over anhydrous MgSO₄. Concentration in vacuo provided a crudeproduct, which was purified by titration, or recrystallization, orsilica gel column chromatography, or Shimadzu automated preparative HPLCSystem.

                        Compound 1001

MS (M + H)⁺ Calcd. 405.1 MS (M + H)⁺ Observ. 405.2 Retention Time 3.33min LC Condition Solvent A 5% Water:95% Methanol:0.1% TFA Solvent B 95%Water:5% Methanol:0.1% TFA Start % B 0 Final % B 100 Gradient Time 4 minFlow Rate 4 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFA ColumnPHENOMENEX-LUNA 4.6 × 50 mm S10                         Compound 1002

MS (M + H)⁺ Calcd. 419.2 MS (M + H)⁺ Observ. 419.2 Retention Time 3.39min LC Condition Solvent A 5% Water:95% Methanol:0.1% TFA Solvent B 95%Water:5% Methanol:0.1% TFA Start % B 0 Final % B 100 Gradient Time 4 minFlow Rate 4 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFA ColumnPHENOMENEX-LUNA 4.6 × 50 mm S10                       Compound 1003

MS (M + H)⁺ Calcd. 453.1 MS (M + H)⁺ Observ. 453.2 Retention Time 3.63min LC Condition Solvent A 5% Water:95% Methanol:0.1% TFA Solvent B 95%Water:5% Methanol:0.1% TFA Start % B 0 Final % B 100 Gradient Time 4 minFlow Rate 4 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFA ColumnPHENOMENEX-LUNA 4.6 × 50 mm S10                       Compound 1004

MS (M + H)⁺ Calcd. 437.2 MS (M + H)⁺ Observ. 437.2 Retention Time 3.59min LC Condition Solvent A 5% Water:95% Methanol:0.1% TFA Solvent B 95%Water:5% Methanol:0.1% TFA Start % B 0 Final % B 100 Gradient Time 4 minFlow Rate 4 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFA ColumnPHENOMENEX-LUNA 4.6 × 50 mm S10                       Compound 1005

MS (M + H)⁺ Calcd. 433.2 MS (M + H)⁺ Observ. 433.2 Retention Time 3.24min LC Condition Solvent A 5% Water:95% Methanol:0.1% TFA Solvent B 95%Water:5% Methanol:0.1% TFA Start % B 0 Final % B 100 Gradient Time 4 minFlow Rate 4 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFA ColumnPHENOMENEX-LUNA 4.6 × 50 mm S10                         Compound 1006

MS (M + H)⁺ Calcd. 433.2 MS (M + H)⁺ Observ. 433.2 Retention Time 3.50min LC Condition Solvent A 5% Water:95% Methanol:0.1% TFA Solvent B 95%Water:5% Methanol:0.1% TFA Start % B 0 Final % B 100 Gradient Time 4 minFlow Rate 4 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFA ColumnPHENOMENEX-LUNA 4.6 × 50 mm S10                           Compound 1007

MS (M + H)⁺ Calcd. 420.2 MS (M + H)⁺ Observ. 420.2 Retention Time 1.66min LC Condition Solvent A 90% Water-10% Methanol-0.1% TFA Solvent B 10%Water-90% Methanol-0.1% TFA Start % B 0 Final % B 100 Gradient Time 2min Flow Rate 4 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFAColumn PHENOMENEX-LUNA 4.6 × 30 mm S10                            Compound 1008

MS (M + H)⁺ Calcd. 468.2 MS (M + H)⁺ Observ. 468.2 Retention Time 1.49min LC Condition Solvent A 5% ACN:95% Water:10 mM Ammonium ActetateSolvent B 95% ACN:5% Water:10 mM Ammonium Actetate Start % B 0 Final % B100 Gradient Time 2 min Flow Rate 4 mL/min Wavelength 220 Solvent PairACN:Water:Ammonium Actetate Column Luna 4.6 × 50 mm S10                          Compound 1009

MS (M + H)⁺ Calcd. 435.2 MS (M + H)⁺ Observ. 435.2 Retention Time 1.99min LC Condition Solvent A 90% Water-10% Methanol-0.1% TFA Solvent B 10%Water-90% Methanol-0.1% TFA Start % B 0 Final % B 100 Gradient Time 2min Flow Rate 4 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFAColumn PHENOMENEX-LUNA 4.6 × 30 mm S10                          Compound 1010

MS (M + H)⁺ Calcd. 434.2 MS (M + H)⁺ Observ. 434.3 Retention Time 1.41min LC Condition Solvent A 90% Water-10% Methanol-0.1% TFA Solvent B 10%Water-90% Methanol-0.1% TFA Start % B 0 Final % B 100 Gradient Time 2min Flow Rate 4 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFAColumn PHENOMENEX-LUNA 4.6 × 30 mm S10                          Compound 1011

MS (M + H)⁺ Calcd. 490.2 MS (M + H)⁺ Observ. 490.3 Retention Time 1.20min LC Condition Solvent A 5% ACN:95% Water:10 mM Ammonium ActetateSolvent B 95% ACN:5% Water:10 mM Ammonium Actetate Start % B 0 Final % B100 Gradient Time 2 min Flow Rate 5 mL/min Wavelength 220 Solvent PairACN:Water:Ammonium Actetate Column PHENOMENEX-LUNA 3.0 × 50 mm S10              Compound 1012

MS (M + H)⁺ Calcd. 380.15 MS (M + H)⁺ Observ. 380.15 Retention Time 1.2min LC Condition Solvent A 10% MeOH:90% Water:0.1% TFA Solvent B 90%MeOH:10% Water:0.1% TFA Start % B 0 Final % B 100 Gradient Time 2 minFlow Rate 5 mL/min Wavelength 220 Solvent Pair MeOH:Water:AmmoniumActetate Column XTERRA MS C18 7 μ 3.0 × 50 mm                 Compound1016

MS (M + H)⁺ Calcd. 367.1 MS (M + H)⁺ Observ. 367.2 Retention Time 1.83min LC Condition Solvent A 90% Water-10% Methanol-0.1% TFA Solvent B 10%Water-90% Methanol-0.1% TFA Start % B 0 Final % B 100 Gradient Time 2min Flow Rate 4 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFAColumn PHENOMENEX-LUNA 4.6 × 30 mm S10                          Compound 1017

MS (M + Na)⁺ Calcd. 413.2 MS (M + H)⁺ Observ. 413.5 Retention Time 1.51min LC Condition Solvent A 90% Water-10% Methanol-0.1% TFA Solvent B 10%Water-90% Methanol-0.1% TFA Start % B 0 Final % B 100 Gradient Time 2min Flow Rate 5 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFAColumn XTERRA ms C18 4.6 × 30 mm                               Compound1018

MS (M + H)⁺ Calcd. 480.1 MS (M + H)⁺ Observ. 480.4 Retention Time 1.84min LC Condition Solvent A 90% Water-10% Methanol-0.1% TFA Solvent B 10%Water-90% Methanol-0.1% TFA Start % B 0 Final % B 100 Gradient Time 2min Flow Rate 5 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFAColumn XTERRA ms C18 4.6 × 30 mm                   Compound 1019

MS (M + Na)⁺ Calcd. 439.1 MS (M + H)⁺ Observ. 439.4 Retention Time 1.77min LC Condition Solvent A 90% Water-10% Methanol-0.1% TFA Solvent B 10%Water-90% Methanol-0.1% TFA Start % B 0 Final % B 100 Gradient Time 2min Flow Rate 5 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFAColumn XTERRA ms C18 4.6 × 30 mm                               Compound1020

MS (M + H)⁺ Calcd. 437.1 MS (M + H)⁺ Observ. 437.2 Retention Time 2.94min LC Condition Solvent A 5% Water:95% Methanol:0.1% TFA Solvent B 95%Water:5% Methanol:0.1% TFA Start % B 0 Final % B 100 Gradient Time 4 minFlow Rate 4 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFA ColumnPHENOMENEX-LUNA 4.6 × 50 mm S10                         Compound 2002

MS (M + H)⁺ Calcd. 483.2 MS (M + H)⁺ Observ. 483.1 Retention Time 1.74min LC Condition Solvent A 90% Water-10% Methanol-0.1% TFA Solvent B 10%Water-90% Methanol-0.1% TFA Start % B 0 Final % B 100 Gradient Time 2min Flow Rate 4 mL/min Wavelength 220 Solvent Pair Water-Methanol-TFAColumn PHENOMENEX-LUNA 4.6 × 30 mm S10                            Compound 2003

MS (M + H)⁺ Calcd. 484.2 MS (M + H)⁺ Observ. 484.4 Retention Time 1.72min LC Condition Solvent A 5% ACN:95% Water:10 mM Ammonium ActetateSolvent B 95% ACN:5% Water:10 mM Ammonium Actetate Start % B 0 Final % B100 Gradient Time 4 min Flow Rate 4 mL/min Wavelength 220 Solvent PairACN:Water:Ammonium Actetate Column PHENOMENEX-LUNA 4.6 × 30 mm S10

Synthesis of Compound 2001: Step 1:

Cyanogen bromide (22 g) was slowly added to a stirred solution ofaniline (10 g) in dry diethyl ether (150 mL) under nitrogen atmosphereat 0° C. The reaction mixture was stirred at room temperature for about3 hours. The reaction mixture was filtered through celite bed and washedwith diethyl ether (3×20 mL). The filtrate was concentrated underreduced pressure to give crude N-phenylcyanamide (8 g) as brown liquid,which was used for further reaction without purification. ¹H NMR(DMSO-d₆): δ 6.97-7.03 (m, 3H), 7.30-7.36 (m, 2H), 10.13 (bs, 1H). MS:117.2 (M−1)⁺.

Step 2:

To a stirred solution of N-phenylcyanamide (8 g) in dry diethyl ether(50 mL), HCl in dry diethyl ether (20 mL) was slowly added undernitrogen atmosphere at 0° C. The reaction mixture was stirred at roomtemperature for about 30 minutes. The salt precipitated was filteredthrough Buckner funnel and washed with diethyl ether (3×20 mL) undernitrogen atmosphere. The HCl salt of N-phenylcyanamide was taken in dryethanol (100 mL), slowly added palladium on carbon (2 g) under nitrogenatmosphere. The reaction mixture was allowed to stir under hydrogenatmosphere using bladder for 16 hours. After completion of the reaction,the reaction mixture was filtered through celite bed and washed withmethanol (3×20 mL). The filtrate was concentrated under reduced pressureto afford the desired N-phenylformimidamide (7 g) as colorless liquid.MS: 119.1 (M−1)⁺.

Step 3:

To a stirred solution of N-benzyl azepinone (5 g) in dry diethyl ether(50 mL), HCl in dry diethyl ether (20 mL) was slowly added undernitrogen atmosphere at 0° C. The reaction mixture was stirred at roomtemperature for about 30 minutes. The salt precipitated was filteredthrough Buckner funnel and washed with diethyl ether (3×20 mL) undernitrogen atmosphere. The HCl salt of N-benzyl azepinone was taken inacetic acid (15 mL) and HBr in acetic acid (15 mL) mixture, bromine (4g) was then slowly added under nitrogen atmosphere. The reaction mixturewas allowed to stir at room temperature for 2 hours. The reactionmixture was concentrated to remove volatiles under reduced pressure andthe residue was diluted with diethyl ether (10 mL). Solid precipitatedout, the solvent was decanted and the process was repeated three to fourtimes. The solid was allowed to dry under reduced pressure to afford1-benzyl-5-bromo-2,3,6,7-tetrahydro-1H-azepin-4-ol as a HBr salt (9 g),which was used further without any purification. ¹H NMR (DMSO-d₆): δ2.6-2.95 (m, 3H), 3.05-3.17 (m, 1H), 3.25-3.41 (m, 1H), 3.45-3.60 (m,2H), 4.43-4.48 (m, 2H), 5.12-5.19 (m, 1H), 7.34-7.55 (m, 5H), 9.96-10.09(bs, 1H). MS: 284.2 (M+1)⁺.

Step 4:

Sodium metal (1.6 g) was added slowly into dry ethanol (100 mL) undernitrogen atmosphere. The reaction mixture was stirred at roomtemperature until all the sodium metal dissolved, beforeN-phenylformimidamide (4 g) was added, followed by1-benzyl-5-bromo-2,3,6,7-tetrahydro-1H-azepin-4-ol (10 g) under nitrogenatmosphere. The reaction mixture was stirred at 80° C. for 16 hoursunder nitrogen atmosphere before being cooled to room temperature. Thereaction mixture was concentrated to remove ethanol under reducedpressure and the residue was diluted with ice cold water (50 mL). Theproduct was extracted with ethyl acetate (3×50 mL) and the combinedorganic layer was washed with brine (50 mL). The organic layer was driedover anhydrous Na₂SO₄ and concentrated using rotary evaporator. Theresulting crude was purified by column chromatography using MeOH/CHCl₃(0.3:9.7) as eluent to afford6-benzyl-1-phenyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepine (700 mg) asbrown liquid. ¹H NMR (DMSO-d₆): δ 2.59-2.62 (m, 2H), 2.75-2.83 (m, 6H),3.76 (s, 2H), 7.24-7.30 (m, 1H), 7.32-7.38 (m, 2H), 7.44-7.50 (m, 4H),7.50-7.52 (m, 1H), 7.52-7.54 (m, 2H), 7.59 (s, 1H). MS: 304.2 (M+1)⁺.

Step 5:

To a stirred solution of6-benzyl-1-phenyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepine (0.65 g) indry methanol (20 mL), palladium hydroxide (0.3 g) was slowly added undernitrogen atmosphere. The reaction mixture was allowed to stir at 3 kgpressure under hydrogen atmosphere for 16 hours. After completion of thereaction, the reaction mixture was filtered through celite bed andwashed with methanol (3×20 mL). The filtrate was concentrated underreduced pressure to afford the desired1-phenyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepine (160 mg) as brownsolid. ¹H NMR (DMSO-d₆): δ 2.57-2.61 (m, 2H), 2.79-2.85 (m, 2H),3.56-3.61 (m, 2H), 3.79-3.85 (m, 2H), 7.35-7.38 (m, 2H), 7.44-7.51 (m,3H), 7.65 (s, 1H). MS: 213.2 (M+1)⁺.

Step 6:

To a stirred solution of2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoaceticacid (200 mg) in dry DMF (5 mL),1-phenyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepine (150 mg) in drydichloromethane (5 mL), 2-chloro-1,3-dimethyl imidazolium chloride (54mg) and iPr₂NEt (0.5 mL) were added. The reaction mixture was stirred atroom temperature for 16 hours, before solvents were removed underreduced pressure. The resulting oil was diluted with dichloromethane (50mL), washed with 10% NaHCO₃ (10 mL) and brine (10 mL). The organic layerwas dried over anhydrous Na₂SO₄ and concentrated using rotaryevaporator. The resulting crude was purified by column chromatographyusing MeOH/CHCl₃ (1.0:9.0) as eluent to afford compound 2001 (30 mg) aswhite solid. ¹H NMR (400 MHz, DMSO-d6): δ 2.50 (s, 3H), 2.70-2.73 (t,1H), 2.76-2.78 (t, 1H), 2.88-2.95 (m, 2H), 3.63-3.65 (t, 2H), 3.82-3.84(m, 2H), 3.94 (s, 3H), 7.35-7.59 (m, 5H), 7.68 (s, 1H), 7.86-7.87 (d,1H), 8.19-8.22 (d, 1H), 9.23 (s, 1H), 12.37 (bs, 1H). MS: 497.2 (M+1)⁺.

Biology Data for the Examples

-   -   “μM” means micromolar;    -   “mL” means milliliter;    -   “μl” means microliter;    -   “mg” means milligram;

The materials and experimental procedures used to obtain the resultsreported in Table 1 are described below.

Cells:

-   -   Virus production—Human embryonic Kidney cell line, 293T (HEK        293T), was propagated in Dulbecco's Modified Eagle Medium        (Invitrogen, Carlsbad, Calif.) containing 10% fetal bovine serum        (FBS, Sigma, St. Louis, Mo.). The human T-cell leukemia cell MT2        (AIDS Research and Reference Reagent Program, Cat. 237) was        propagated in RPMI 1640 (Invitrogen, Carlsbad, Calif.)        containing 10% fetal bovine serum (FBS, Hyclone, Logan, Utah)    -   Virus infection—Single-round infectious reporter virus was        produced by co-transfecting HEK 293T cells with plasmide        expressing the HIV-1 LAI envelope along with a plasmid        containing an HIV-1 LAI proviral cDNA with the envelope gene        replaced by a firefly luciferase reporter gene (Chen et al., Ref        41). Transfections were performed using lipofectAMINE PLUS        reagent as described by the manufacturer (Invitrogen, Carlsbad,        Calif.).

Experimental Procedure

-   1. MT2 cells were plated in black, 384 well plates at a cell density    of 5×10³ cells per well in 25 μl RPMI 1640 containing 10% FBS.-   2. Compound (diluted in dimethylsulfoxide and growth medium) was    added to cells at 12.5 μl/well, so that the final assay    concentration would be ≦50 nM.-   3. 12.5 μl of single-round infectious reporter virus in Dulbecco's    Modified Eagle

Medium was added to the plated cells and compound at an approximatemultiplicity of infection (MOI) of 0.01, resulting in a final volume of50 μl per well.

-   4. Virus-infected cells were incubated at 37 degrees Celsius in a    CO₂ incubator and harvested 72 h after infection.-   5. Viral infection was monitored by measuring luciferase expression    in the infected cells using a luciferase reporter gene assay kit    (Steady-Glo, Promega, Madison, Wis.) as described by the    manufacturer. Luciferase activity was then quantified by measuring    luminescence using an EnVision Multilabel Plate Readers    (PerkinElmer, Waltham, Mass.).-   6. The percent inhibition for each compound was calculated by    quantifying the level of luciferase expression in cells infected in    the presence of each compound as a percentage of that observed for    cells infected in the absence of compound and subtracting such a    determined value from 100.-   7. An EC₅₀ provides a method for comparing the antiviral potency of    the compounds of the invention. The effective concentration for    fifty percent inhibition (EC₅₀) was calculated with the Microsoft    Excel Xlfit curve fitting software. For each compound, curves were    generated from percent inhibition calculated at 10 different    concentrations by using a four parameter logistic model (model 205).    The EC₅₀ data for the compounds is shown in Table 2. Table 1 is the    key for the data in Table 2.

TABLE1 Biological Data Key for EC₅₀ Compounds with Compounds withEC₅₀ >0.5 μM EC₅₀ <0.5 μM Group B Group A

TABLE 2 Compd. EC₅₀ Number Structure Group from Table 1 1001

A 38.15 nM 1002

A 1003

B 1004

B 1005

B 1006

A 1007

A 1008

A 18.92 nM 1009

A 1010

A 41.80 nM 1011

A 1012

A 1013

B 1014

B 756.60 nM  1015

B 1016

B 1017

B 1018

B 1019

B 1020

A 2001

A  0.09 nM 2002

A  0.92 nM 2003

A

The foregoing description is merely illustrative and should not beunderstood to limit the scope or underlying principles of the inventionin any way. Indeed, various modifications of the invention, in additionto those shown and described herein, will become apparent to thoseskilled in the art from the following examples and the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims.

What is claimed is:
 1. One or more compounds of Formula I, includingpharmaceutically acceptable salts thereof:

wherein A is selected from the group consisting of:

wherein a, b, c, d and e are independently selected from the groupconsisting of hydrogen, halogen, cyano, nitro, COOR⁵⁶, XR⁵⁷, NA¹A²,C(O)R⁷, C(O)NR⁵⁵R⁵⁶, B, Q, and E; B is selected from the groupconsisting of —C(═NR⁴⁶)(R⁴⁷), C(O)NR⁴⁰R⁴¹ aryl, heteroaryl,heteroalicyclic, S(O)₂R⁸, S(O)₂NR⁴⁰R⁴¹, C(O)R⁷, XR^(8a),(C₁₋₆)alkylNR⁴⁰R⁴¹, (C₁₋₆)alkylCOOR^(8b); wherein said aryl, heteroaryl,and heteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to three same or different substituentsselected from the group F; wherein aryl is napthyl or substitutedphenyl; wherein heteroaryl is a mono or bicyclic system which containsfrom 3 to 7 ring atoms for a mono cyclic system and up to 12 atoms in afused bicyclic system, including from 1 to 4 heteroatoms; whereinheteroalicyclic is a 3 to 7 membered mono cyclic ring which may containfrom 1 to 2 heteroatoms in the ring skeleton and which may be fused to abenzene or pyridine ring; Q is selected from the group consisting of(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl and (C₂₋₆)alkenyl; wherein said(C₁₋₆)alkyl and (C₂₋₆)alkenyl are optionally substituted with one tothree same or different halogens or from one to three same or differentsubstituents selected from the group consisting of C(O)NR⁵⁵R⁵⁶, hydroxy,cyano and XR⁵⁷; E is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl and (C₂₋₆)alkenyl; wherein said (C₁₋₆)alkyl and(C₂₋₆)alkenyl are independently optionally substituted with a memberselected from the group consisting of phenyl, heteroaryl, SMe, SPh,—C(O)NR⁵⁶R⁵⁷, C(O)R⁵⁷, SO₂(C₁₋₆)alkyl and SO₂Ph; wherein heteroaryl is amonocyclic system which contains from 3 to 7 ring atoms, including from1 to 4 heteroatoms; F is selected from the group consisting of(C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, aryloxy, (C₁₋₆)thioalkoxy, cyano, halogen, nitro,—C(O)R⁵⁷, benzyl, —NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²C(O)—(C₃₋₆)cycloalkyl,—NR⁴²C(O)-aryl, —NR⁴²C(O)-heteroaryl, —NR⁴²C(O)-heteroalicyclic, a 4, 5,or 6 membered ring cyclic N-lactam, —NR⁴²S(O)₂—(C₁₋₆)alkyl,—NR⁴²S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴²S(O)2-aryl, —NR⁴²S(O)₂-heteroaryl,—NR⁴²S(O)2-heteroalicyclic, S(O)₂(C₁₋₆)alkyl, S(O)₂aryl, —S(O)2 NR⁴²R⁴³,NR⁴²R⁴³, (C₁₋₆)alkylC(O)NR⁴²R⁴³, C(O)NR⁴²R⁴³, NHC(O)NR⁴²R⁴³,OC(O)NR⁴²R⁴³, NHC(O)OR⁵⁴, (C₁₋₆)alkylNR⁴²R⁴³, COOR⁵⁴, and(C₁₋₆)alkylCOOR⁵⁴; wherein said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, aryl,heteroaryl, heteroalicyclic, (C₁₋₆)alkoxy, and aryloxy, are optionallysubstituted with one to nine same or different halogens or from one tofive same or different substituents selected from the group G; whereinaryl is phenyl; heteroaryl is a monocyclic system which contains from 3to 7 ring atoms, including from 1 to 4 heteroatoms; heteroalicyclic isselected from the group consisting of aziridine, azetidine, pyrrolidine,piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine, andmorpholine; G is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₇)cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, aryloxy, cyano, halogen, nitro, —C(O)R⁵⁷, benzyl,—NR⁴⁸C(O)—(C₁₋₆)alkyl, —NR⁴⁸C(O)—(C₃₋₆)cycloalkyl, —NR⁴⁸C(O)-aryl,—NR⁴⁸C(O)-heteroaryl, —NR⁴⁸C(O)-heteroalicyclic, a 4, 5, or 6 memberedring cyclic N-lactam, —NR⁴⁸S(O)₂—(C₁₋₆)alkyl,—NR⁴⁸S(O)₂—(C₃₋₆)cycloalkyl, —NR⁴⁸S(O)2-aryl, —NR⁴⁸S(O)₂-heteroaryl,—NR⁴⁸S(O)2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR⁴⁸R⁴⁹,(C₁₋₆)alkyl C(O)NR⁴⁸R⁴⁹, C(O)NR⁴⁸R⁴⁹, NHC(O)NR⁴⁸R⁴⁹, OC(O)NR⁴⁸R⁴⁹,NHC(O)OR^(54′), (C₁₋₆)alkylNR⁴⁸R⁴⁹, COOR⁵⁴, and (C₁₋₆)alkylCOOR⁵⁴;wherein aryl is phenyl; heteroaryl is a monocyclic system which containsfrom 3 to 7 ring atoms, including from 1 to 4 heteroatoms;heteroalicyclic is selected from the group consisting of aziridine,azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran,tetrahydropyran, azepine, and morpholine; R⁷ is selected from the groupconsisting of (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₃₋₇)cycloalkyl, aryl,heteroaryl, and heteroalicyclic; wherein said aryl, heteroaryl, andheteroalicyclic are optionally substituted with one to three same ordifferent halogens or with from one to three same or differentsubstituents selected from the group F; wherein for R⁷, R⁸, R^(8a),R^(8b) aryl is phenyl; heteroaryl is a mono or bicyclic system whichcontains from 3 to 7 ring atoms for mono cyclic systems and up to 10atoms in a bicyclic system, including from 1 to 4 heteroatoms; whereinheteroalicyclic is selected from the group consisting of aziridine,azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran,tetrahydropyran, azepine, and morpholine; R⁸ is selected from the groupconsisting of hydrogen, (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₂₋₆)alkenyl,(C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl, aryl, heteroaryl, andheteroalicyclic; wherein said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₂₋₆)alkenyl, (C₃₋₇)cycloalkenyl, (C₂₋₆)alkynyl, aryl, heteroaryl, andheteroalicyclic are optionally substituted with one to six same ordifferent halogens or from one to five same or different substituentsselected from the group F or (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano,phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy,halogen, benzyl, primary amine, secondary amine, tertiary amine,ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde,ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acylsulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoricacid, boronic ester, boronic acid, squarate, squaric acid, oxime,hydrazine, peroxide, among which ether, peroxide, thioether, secondaryamine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic; heteroaryl is selected fromthe group consisting of furanyl, thienyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl; R^(8a) is a member selected from the group consisting ofaryl, heteroaryl, and heteroalicyclic; wherein each member isindependently optionally substituted with one to six same or differenthalogens or from one to five same or different substituents selectedfrom the group F; R^(8b) is selected from the group consisting ofhydrogen, (C₁₋₆)alkyl and phenyl; X is selected from the groupconsisting of CR₁R₂, NH or NCH₃, O, and S; R⁴⁰ and R⁴¹ are independentlyselected from the group consisting of (a) hydrogen; (b) (C₁₋₆)alkyl or(C₃₋₇)cycloalkyl substituted with one to three same or differenthalogens or from one to two same or different substituents selected fromthe group F or different functional groups: (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl, heteroalicyclic,hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine, secondary amine,tertiary amine, ammonium, nitro, thiol, thioether, alcohol, ether, acid,aldehyde, ketone, amide, amidine, guanidine, sulfone, sulfonamide,sulfamide, acyl sulfamide, sulfate, sulfuric acid, sulfamic acid,phosphate, phosphoric acid, boronic ester, boronic acid, squarate,squaric acid, oxime, hydrazine, peroxide, among which ether, peroxide,thioether, secondary amine, tertiary amine, ammonium, ester, ketone,amide, amidine, oxime, hydrazine can be either acyclic or cyclic;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl; and (c) (C₁₋₆)alkoxy, aryl, heteroaryl orheteroalicyclic; or R⁴⁰ and R⁴¹ taken together with the nitrogen towhich they are attached form a member selected from the group consistingof aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine,piperidine, azepine, and morpholine; and wherein said aryl, heteroaryl,and heteroalicyclic are optionally substituted with one to three same ordifferent halogens or from one to two same or different substituentsselected from the group F; wherein for R⁴⁰ and R⁴¹ aryl is phenyl;heteroaryl is a monocyclic system which contains from 3 to 6 ring atoms,including from 1 to 4 heteroatoms; heteroalicyclic is selected from thegroup consisting of aziridine, azetidine, pyrrolidine, piperazine,piperidine, tetrahydrofuran, tetrahydropyran, azepine, and morpholine;provided when B is C(O)NR⁴⁰R⁴¹, at least one of R⁴⁰ and R⁴¹ is notselected from groups (a) or (b); R⁴² and R⁴³ are independently selectedfrom the group consisting of hydrogen, (C₁₋₆)alkyl, allyl, (C₁₋₆)alkoxy,(C₃₋₇)cycloalkyl, aryl, heteroaryl and heteroalicyclic; or R⁴² and R⁴³taken together with the nitrogen to which they are attached form amember selected from the group consisting of aziridine, azetidine,pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine, andmorpholine; and wherein said (C₁₋₆)alkyl, (C₁₋₆)alkoxy,(C₃₋₇)cycloalkyl, aryl, heteroaryl, and heteroalicyclic are optionallysubstituted with one to three same or different halogens or from one totwo same or different substituents selected from the group G ordifferent functional groups: (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano,phenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy,halogen, benzyl, primary amine, secondary amine, tertiary amine,ammonium, nitro, thiol, thioether, alcohol, ether, acid, aldehyde,ketone, amide, amidine, guanidine, sulfone, sulfonamide, sulfamide, acylsulfamide, sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoricacid, boronic ester, boronic acid, squarate, squaric acid, oxime,hydrazine, peroxide, among which ether, peroxide, thioether, secondaryamine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic; heteroaryl is selected fromthe group consisting of furanyl, thienyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl; wherein for R⁴² and R⁴³ aryl is phenyl; heteroaryl is amonocyclic system which contains from 3 to 6 ring atoms, including from1 to 4 heteroatoms; heteroalicyclic is a member selected from the groupconsisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine,tetrahydrofuran, tetrahydropyran, azepine, and morpholine; R⁴⁶ isselected from the group consisting of H, phenyl, aryl, heteroaryl and(C₁₋₆)alkyl, OR⁵⁷, and NR⁵⁵R⁵⁶; R⁴⁷ is selected from the groupconsisting of H, amino, hydroxyl, phenyl, aryl, heteroaryl and(C₁₋₆)alkyl; R⁴⁸ and R⁴⁹ are independently selected from the groupconsisting of hydrogen, (C₁₋₆)alkyl, phenyl, aryl and heteroaryl; R⁵⁰ isselected from the group consisting of H, (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl,and benzyl; wherein each of said (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl andbenzyl are optionally substituted with one to three same or different(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, cyano, phenyl, aryl, heteroaryl,heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl, primary amine,secondary amine, tertiary amine, ammonium, nitro, thiol, thioether,alcohol, ether, acid, aldehyde, ketone, amide, amidine, guanidine,sulfone, sulfonamide, sulfamide, acyl sulfamide, sulfate, sulfuric acid,sulfamic acid, phosphate, phosphoric acid, boronic ester, boronic acid,squarate, squaric acid, oxime, hydrazine, peroxide, among which ether,peroxide, thioether, secondary amine, tertiary amine, ammonium, ester,ketone, amide, amidine, oxime, hydrazine can be either acyclic orcyclic; heteroaryl is selected from the group consisting of furanyl,thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl,pyrazinyl, pyridazinyl, and pyrimidinyl R⁵⁴ is selected from the groupconsisting of hydrogen and (C₁₋₆)alkyl; R^(54′) is (C₁₋₆)alkyl; R⁵⁵ andR⁵⁶ are independently selected from the group consisting of hydrogen and(C₁₋₆)alkyl; and R⁵⁷ is selected from the group consisting of hydrogen,(C₁₋₆)alkyl, aryl, heteroaryl; and A¹ and A² are independently selectedfrom hydrogen, (C₁₋₆)alkyl, aryl, heteroaryl, SO₂D¹, SO₂ND²D³, COD⁴,COCOD⁴, COOD⁴, COND⁵D⁶, COCOND⁵D⁶, COCOOD⁴, C(═ND⁷)D⁸, C(═ND⁹)ND¹⁰D¹¹;A¹ and A² can either never connect with each other, or conjoin to form aring structure; D¹, D², D³, D⁴, D⁵, D⁶, D⁷, D⁸, D⁹, D¹⁰, and D¹¹ areeach independently selected from the group consisting of H, C₁-C₅₀alkyl, C₃-C₅₀ cycloalkyl, C₃-C₅₀ alkenyl, C₄-C₅₀ cycloalkenyl, phenyl,heteroaryl, C₃-C₅₀ amide and C₃-C₅₀ ether; heteroaryl is selected fromthe group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl,benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl,1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyland triazolyl; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₃-C₂₀ alkenyl or the carbon-carbontriple bond of said C₃-C₂₀ alkynyl are not the point of attachment tothe nitrogen to which D², D³, D⁵, D⁶, D⁷, D⁹, D¹⁰, and D¹¹ is attached;wherein said C₁-C₅₀ alkyl, C₃-C₅₀ cycloalkyl, C₃-C₅₀ alkenyl, C₄-C₅₀cycloalkenyl, aryl, phenyl, heteroaryl, C₃-C₅₀ amide and C₃-C₅₀ ether isoptionally substituted with one to three same or different of thefollowing functionalities: (C₁₋₆)alkyl, (C₃₋₆ cycloalkyl, cyano, phenyl,aryl, heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen,benzyl, primary amine, secondary amine, tertiary amine, ammonium, nitro,thiol, thioether, alcohol, ether, acid, aldehyde, ketone, amide,amidine, guanidine, sulfone, sulfonamide, sulfamide, acyl sulfamide,sulfate, sulfuric acid, sulfamic acid, phosphate, phosphoric acid,boronic ester, boronic acid, squarate, squaric acid, oxime, hydrazine,peroxide and steroid, among which ether, peroxide, thioether, secondaryamine, tertiary amine, ammonium, ester, ketone, amide, amidine, oxime,hydrazine can be either acyclic or cyclic; Z is selected from the groupof:

Z is also selected from the group of:

f and g are selected from the group consisting of H, (C₁-C₄) alkyl, and(C₃-C₆) cycloalkyl group, and wherein said alkyl or cycloalkyl group isoptionally substituted with one to three substitutions selected from thegroup of F, OH, OR, NR₁R₂, COOR, and CONR₁R₂; and wherein f and g can beconnected by carbon, oxygen, nitrogen or sulfur atom to form a ring; hand i are selected from the group consisting of H, (C₁-C₄) alkyl, and(C₃-C₆) cycloalkyl group. wherein said alkyl or cycloalkyl group isoptionally substituted with one to three substitutions selected from thegroup of F, OH, OR, NR₁R₂, COOR, and CONR₁R₂; and wherein h and i can beconnected by a carbon, oxygen, nitrogen or sulfur atom to form a ring; jis selected from the group consisting of H, F, (C₁-C₄) alkyl, and(C₃-C₆) cycloalkyl group, and wherein said alkyl or cycloalkyl group isoptionally substituted with one to three substitutions selected from thegroup of F, OH, OR, NR₁R₂, COOR, and CONR₁R₂; l is selected from thegroup consisting of hydrogen, (C₁₋₆)alkyl, (C₁₋₆)alkynyl, (C₃₋₆)cycloalkyl, halogen, cyano, —CONR³²R³³, —SO2 R³², COR³², COOR⁸,tetrahydrofuryl, pyrrolidinyl, phenyl and heteroaryl; wherein said(C₁₋₆)alkyl, (C₁₋₆)alkynyl, phenyl and heteroaryl are each independentlyoptionally substituted with one to three same or different membersselected from the group U; heteroaryl is selected from the groupconsisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl; m is selected from the group consisting of H, (C₁-C₄) alkyloptionally substituted with one to three substitutions selected from F,OH, OR, NR₁R₂, COOR, CONR₁R₂, (C₃-C₆) cycloalkyl optionally substitutedwith one to three substitutions selected from F, OH, OR, NR₃R₄, COOR,CON R₃R₄, OR, halogen (attached to carbon only), and Group X; n, o, p,q, r, s, t and u are selected from the group consisting of H, F, (C₁-C₄)alkyl, and (C₃-C₆) cycloalkyl group, and wherein said alkyl orcycloalkyl group is optionally substituted with one to threesubstitutions selected from the group of F, OH, OR, NR₁R₂, COOR, andCONR₁R₂; and wherein n, o, p, q, r, s, t and u can be connected bycarbon, oxygen, nitrogen or sulfur atom to form a ring; u and v areselected from the group consisting of H, OH, NR_(1a)R_(2a), (C₁-C₄)alkyl optionally substituted with one to three substitutions selectedfrom F, OH, OR, NR₁R₂, COOR, CONR₁R₂, (C₃-C₆) cycloalkyl optionallysubstituted with one to three substitutions selected from F, OH, OR,NR₃R₄, COOR, CON R₃R₄, OR, halogen (attached to carbon only), and GroupX; X₁ is selected from the group consisting of NH or NCH₃, O, and S; Aris selected from the group consisting of phenyl and heteroaryl; whereinsaid phenyl and heteroaryl are independently optionally substituted withone to three same or different halogens or from one to three same ordifferent substituents selected from Group Y; heteroaryl is selectedfrom the group consisting of pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, furanyl, thienyl, thiazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, and triazolyl; Group U is selectedfrom the group consisting of (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl cyano,trimethylsilyl, phenyl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, halogen, benzyl, —NR⁴²C(O)—(C₁₋₆)alkyl, —NR⁴²R⁴³,—C(O)NR⁴²R²⁴³, morpholino, nitro, —S(C₁₋₆)alkyl, —SPh, NR⁴²S(O)₂-alkyl,piperazinyl, N-Me piperazinyl, (CH2)_(n)COOR⁵⁴ and —CONR⁴²R⁴³; whereinsaid (C₁₋₆)alkyl, heteroaryl, or phenyl is optionally substituted withone to three same or different halogens or one to three methyl groups;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl; heteroalicyclic is selected from the groupconsisting of aziridine, azetidine, pyrrolidine, piperazine, N-methylpiperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine andmorpholine; Group X is selected from the group consisting of phenyl andheteroaryl; wherein said phenyl and heteroaryl are independentlyoptionally substituted with one to three same or different halogens orfrom one to three same or different substituents selected from Group D;heteroaryl is selected from the group consisting of pyridinyl,pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, andtriazolyl; Group Y is selected from the group consisting of OH, OR,NR₁R₂, CN, COOR, CONR₁R₂, (C₁-C₄) alkyl, (C₃-C₆) cycloalkyl, and whereinsaid alkyl or cycloalkyl group is optionally substituted with one tothree substitutions selected from the group of F, OH, OR, NR₁R₂, COOR,and CONR₁R₂; R, R₁, R₂, R_(1a) and R_(2a) are independently H, (C₁-C₄)alkyl, (C₃-C₆) cycloalkyl group; wherein said alkyl or cycloalkyl groupis optionally substituted with one to three substitutions selected fromF, OH, OR, NR₃R₄, COOR, CON R₃R₄; and wherein R₁ and R₂ can be connectedby carbon, oxygen, nitrogen or sulfur atom to form a ring; and R₃ and R₄are independently H, (C₁-C₄) alkyl, (C₃-C₆) cycloalkyl group.


2. A compound which is selected from the group of: includingpharmaceutically acceptable salts thereof.
 3. A compound which isselected from

including pharmaceutically acceptable salts thereof.
 4. A pharmaceuticalcomposition which comprises an antiviral effective amount of one or moreof the compounds of Formula I as claimed in claim 2, together with oneor more pharmaceutically acceptable carriers, excipients and/ordiluents.
 5. The pharmaceutical composition of claim 4, useful fortreating infection by HIV, which additionally comprises an antiviraleffective amount of an AIDS treatment agent selected from the groupconsisting of: (a) an AIDS antiviral agent; (b) an anti-infective agent;(c) an immunomodulator; and (d) another HIV entry inhibitor.
 6. A methodfor treating a mammal infected with the HIV virus comprisingadministering to said mammal an antiviral effective amount of a compoundof Formula I as claimed in claim 2, and one or more pharmaceuticallyacceptable carriers, excipients and/or diluents.
 7. The method of claim6, comprising administering to said mammal an antiviral effective amountof a compound of Formula I, in combination with an antiviral effectiveamount of an AIDS treatment agent selected from the group consisting ofan AIDS antiviral agent; an anti-infective agent; an immunomodulator;and another HIV entry inhibitor.